GenVue Discovery
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Showing variants that contain the term
Below are conditions that were reviewed by an expert panel and/or are in the Genetic Testing Registry (GTR) according to ClinVar. The data presented does not diagnose disease and has no guarantees of reporting accuracy. We report heterozygous variants as yellow and homozygous variants as red. A red or yellow variant does not necessarily mean one has or carries a condition or disease. This is for research and educational purposes only.
Gene:
MTHFR
Variant:
c.665C>T
(p.Ala222Val)
rsID: rs1801133
Ref Allele: G
Alt Allele: A
Freq: 28.9739%
CADD: 27.5
ClinVar Submissions (10)
Gastrointestinal stromal tumors are mesenchymal tumors found in the gastrointestinal tract that originate from the interstitial cells of Cajal, the pacemaker cells that regulate peristalsis in the digestive tract. Approximately 70% of GISTs develop in the stomach, 20% in the small intestine, and less than 10% in the esophagus, colon, and rectum. GISTs are typically more cellular than other gastrointestinal sarcomas. They occur predominantly in patients who are 40 to 70 years old but in rare cases may occur in younger persons (Miettinen et al., 1999, 1999). GISTs can also be seen in neurofibromatosis-1 (NF1; 162200) due to mutations in the NF1 gene, and are thus distinct from the GISTs described here. Sandberg and Bridge (2002) reviewed the cytogenetics and molecular genetics of gastrointestinal stromal tumors. Coffey et al. (2007) reviewed the clinical features, pathogenesis, and molecular treatments of Menetrier disease (137280) and GIST, both of which are hyperproliferative disorders of the stomach caused by dysregulated receptor tyrosine kinases.
Last Evaluated: Nov 22, 2018
Review Status: reviewed by expert panel
Number of Submitters: 10
Clinical Significance: Conflicting interpretations of pathogenicity, other, risk factor
Assembly: GRCh38
Chromosome/Position: 1:11796321
OMIM Allelic Variant: 607093.0003
Methylenetetrahydrofolate Reductase (MTHFR) Deficiency is the most common genetic cause of elevated levels of homocysteine in the plasma (hyperhomocysteinemia). The MTHFR enzyme plays an important role in processing amino acids, specifically, the conversion of homocysteine to methionine. Genetic variations in the MTHFR gene can lead to impaired function or inactivation of this enzyme, which results in mildly elevated levels of homocysteine, especially in individuals who are also deficient in folate. In these individuals, a daily supplement of low dose folic acid may reduce and often normalize their homocysteine levels, but this has not been demonstrated to improve health outcomes. A common genetic variant in the MTHFR gene is a 677C>T polymorphism (NM_005957.4:c.665C>T, rs1801133). This variant encodes a thermolabile enzyme that is less active at higher temperatures. Individuals who carry two copies of this variant (“TT homozygous”) tend to have higher homocysteine levels and lower serum folate levels compared to controls. More than 25% of Hispanics and around 10-15% of North America Caucasians are estimated to be homozygous for the “thermolabile” variant (TT genotype). The TT genotype is least common in individuals of African descent (6%). Another common MTHFR variant, 1298A>C (NM_005957.4:c.1286A>C, rs1801131), does not cause increased homocysteine levels in heterozygous or homozygous individuals, but combined heterozygosity of 1298A>C and 677C>T results in an outcome similar to TT homozygous individuals. Until recently, it was thought that MTHFR deficiency, by causing elevated homocysteine levels, led to an increased risk of venous thrombosis, coronary heart disease, and recurrent pregnancy loss. However, more recent analysis has not found an association between elevated homocysteine levels and the risk of venous thrombosis or the risk of coronary heart disease. MTHFR polymorphism genotyping should not be ordered as part of the clinical evaluation for thrombophilia, recurrent pregnancy loss, or for at-risk family members. Rarely, more severe variants in the MTHFR gene can be a cause of an autosomal recessive inborn error or metabolism where extremely high levels of homocysteine accumulate in the urine and plasma. This can cause developmental delay, eye disorders, thrombosis, and osteoporosis. But more commonly, homocystinuria is caused by variants in a different gene (cystathionine beta-synthase, CBS).
Last Evaluated: Nov 22, 2018
Review Status: reviewed by expert panel
Number of Submitters: 10
Clinical Significance: Conflicting interpretations of pathogenicity, other, risk factor
Assembly: GRCh38
Chromosome/Position: 1:11796321
OMIM Allelic Variant: 607093.0003
In a review article on the genetic predisposition to gastric cancer, Bevan and Houlston (1999) concluded that several genes may be associated with an increased risk of gastric cancer. Gastric cancer is a manifestation of a number of inherited cancer predisposition syndromes, including hereditary nonpolyposis colon cancer (HNPCC1; see 120435), familial adenomatous polyposis (FAP; 175100), Peutz-Jeghers syndrome (PJS; 175200), Cowden disease (CD; 158350), and the Li-Fraumeni syndrome (151623). See also hereditary diffuse gastric cancer (HDGC; 137215). Canedo et al. (2007) provided a review of genetic susceptibility to gastric cancer in patients infected with Helicobacter pylori (see 600263).
Last Evaluated: Nov 22, 2018
Review Status: reviewed by expert panel
Number of Submitters: 10
Clinical Significance: Conflicting interpretations of pathogenicity, other, risk factor
Assembly: GRCh38
Chromosome/Position: 1:11796321
OMIM Allelic Variant: 607093.0003
Neural tube defects have a birth incidence of approximately 1 in 1,000 in American Caucasians and are the second most common type of birth defect after congenital heart defects. The most common NTDs are open spina bifida (myelomeningocele) and anencephaly (206500) (Detrait et al., 2005). Women with elevated plasma homocysteine, low folate, or low vitamin B12 (cobalamin) are at increased risk of having a child with a neural tube defect (O'Leary et al., 2005). Motulsky (1996) cited evidence from the Centers for Disease Control ( Anonymous, 1992) that folic acid given before and during the first 4 weeks of pregnancy can prevent 50% or more of neural tube defects. Botto et al. (1999) and Detrait et al. (2005) provided reviews of neural tube defects. De Marco et al. (2006) provided a detailed review of neurulation and the possible etiologies of neural tube defects.
Last Evaluated: Nov 22, 2018
Review Status: reviewed by expert panel
Number of Submitters: 10
Clinical Significance: Conflicting interpretations of pathogenicity, other, risk factor
Assembly: GRCh38
Chromosome/Position: 1:11796321
OMIM Allelic Variant: 607093.0003
Formation of a blood clot (thrombus) inside a vein, causing the obstruction of blood flow.
Last Evaluated: Nov 22, 2018
Review Status: reviewed by expert panel
Number of Submitters: 10
Clinical Significance: Conflicting interpretations of pathogenicity, other, risk factor
Assembly: GRCh38
Chromosome/Position: 1:11796321
OMIM Allelic Variant: 607093.0003
Last Evaluated: Nov 22, 2018
Review Status: reviewed by expert panel
Number of Submitters: 10
Clinical Significance: Conflicting interpretations of pathogenicity, other, risk factor
Assembly: GRCh38
Chromosome/Position: 1:11796321
OMIM Allelic Variant: 607093.0003
Last Evaluated: Nov 22, 2018
Review Status: reviewed by expert panel
Number of Submitters: 10
Clinical Significance: Conflicting interpretations of pathogenicity, other, risk factor
Assembly: GRCh38
Chromosome/Position: 1:11796321
OMIM Allelic Variant: 607093.0003
Last Evaluated: Nov 22, 2018
Review Status: reviewed by expert panel
Number of Submitters: 10
Clinical Significance: Conflicting interpretations of pathogenicity, other, risk factor
Assembly: GRCh38
Chromosome/Position: 1:11796321
OMIM Allelic Variant: 607093.0003
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Nov 22, 2018
Review Status: reviewed by expert panel
Number of Submitters: 10
Clinical Significance: Conflicting interpretations of pathogenicity, other, risk factor
Assembly: GRCh38
Chromosome/Position: 1:11796321
OMIM Allelic Variant: 607093.0003
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Nov 22, 2018
Review Status: reviewed by expert panel
Number of Submitters: 10
Clinical Significance: Conflicting interpretations of pathogenicity, other, risk factor
Assembly: GRCh38
Chromosome/Position: 1:11796321
OMIM Allelic Variant: 607093.0003
Insufficiently evaluated pharmacogenetic — this is a.k.a. C677T and Rs1801133. Modulates toxicity of methotrexate in patients.
Expert Reviewed Clinically Significant Conflicting/Uncertain
Hetero
Gene:
AMPD1
Variant:
c.133C>T
(p.Gln45Ter)
rsID: rs17602729
Ref Allele: G
Alt Allele: A
Freq: 8.0697%
CADD: 36
ClinVar Submissions (6)
Myoadenylate deaminase deficiency (MMDD) is an autosomal recessive condition that can manifest as exercise-induced muscle pain, occasionally associated with rhabdomyolysis and/or increased serum creatine kinase, or even infantile hypotonia. However, the finding of homozygous mutations among asymptomatic individuals have suggested to some (e.g., Verzijl et al., 1998) that AMPD1 deficiency may be a harmless entity (summary by Castro-Gago et al., 2011). Genetta et al. (2001) stated that AMPD1 deficiency is the most prevalent genetic disease in humans, the number of people heterozygous approaching 10% of Caucasians and individuals of African descent (Sabina et al., 1989). A small percentage of homozygous-deficient individuals, approximately 1.8% of the population, display symptoms of chronic fatigue and lost productivity as well as a predisposition to stress-related ailments, including heart disease and stroke, according to Genetta et al. (2001).
Last Evaluated: Jun 27, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity, other
Assembly: GRCh38
Chromosome/Position: 1:114693436
OMIM Allelic Variant: 102770.0001
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jun 27, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity, other
Assembly: GRCh38
Chromosome/Position: 1:114693436
OMIM Allelic Variant: 102770.0001
Low clinical importance, Likely pathogenic — Causes Adenosine Deaminase Deficiency in a recessive manner. Most of the time individuals do not report symptoms, but when symptoms do exist they to be post-exercise symptoms of muscle weakness, muscle pain, and getting tired more quickly.
Expert Reviewed Clinically Significant Conflicting/Uncertain
Hetero
Below are drug responses that were reviewed by an expert panel according to ClinVar. The data presented has no guarantees of reporting accuracy. Heterozygous variants are reported as yellow and homozygous variants as red. Reference alleles may be modified to match risk. While a red or yellow variant could indicate a suboptimal response to drug, it doesn't necessarily mean one won't respond well to it. This is for research and educational purposes only.
Gene:
CYP19A1
Variant:
c.*161T>G
rsID: rs4646
Ref Allele: A
Alt Allele: C
Freq: 70.0545%
CADD: 0.652
ClinVar Submissions (2)
Last Evaluated: Feb 06, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 15:51210647
Last Evaluated: Feb 06, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 15:51210647
Last Evaluated: Feb 06, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 15:51210647
Last Evaluated: Feb 06, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 15:51210647
Last Evaluated: Feb 06, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 15:51210647
Last Evaluated: Feb 06, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 15:51210647
Last Evaluated: Feb 06, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 15:51210647
Last Evaluated: Feb 06, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 15:51210647
Last Evaluated: Feb 06, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 15:51210647
Last Evaluated: Feb 06, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 15:51210647
Last Evaluated: Feb 06, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 15:51210647
Insufficiently evaluated pharmacogenetic — associated with response to a drug letrozole in cancer patients
Expert Reviewed drug response
Homo
Gene:
COMT
Variant:
c.472G>A
(p.Val158Met)
rsID: rs4680
Ref Allele: G
Alt Allele: A
Freq: 42.4264%
CADD: 12.4
ClinVar Submissions (3)
Last Evaluated: Dec 20, 2017
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 22:19963748
OMIM Allelic Variant: 116790.0001
Last Evaluated: Dec 20, 2017
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 22:19963748
OMIM Allelic Variant: 116790.0001
Last Evaluated: Dec 20, 2017
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 22:19963748
OMIM Allelic Variant: 116790.0001
Insufficiently evaluated pathogenic — A codominant allele affecting COMT enzyme activity, considered a benign functional polymorphism. Some claims of association with schizophrenia, Possibly provides advantage in memory and attention tasks ("worrier strategy").
Expert Reviewed drug response
Homo
Gene:
SOD2
Variant:
c.47T>C
(p.Val16Ala)
rsID: rs4880
Ref Allele: A
Alt Allele: G
Freq: 45.7529%
CADD: 12.94
ClinVar Submissions (2)
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 6:159692840
OMIM Allelic Variant: 147460.0001
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 6:159692840
OMIM Allelic Variant: 147460.0001
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 6:159692840
OMIM Allelic Variant: 147460.0001
Expert Reviewed drug response
Hetero
Gene:
GNB3
Variant:
c.825C>T
(p.Ser275=)
rsID: rs5443
Ref Allele: C
Alt Allele: T
Freq: 46.124%
CADD: 0.665
ClinVar Submissions (1)
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 12:6845711
Expert Reviewed drug response
Hetero
Gene:
VKORC1
Variant:
c.*134G>A
rsID: rs7294
Ref Allele: C
Alt Allele: T
Freq: 38.4851%
CADD: 1.59
ClinVar Submissions (2)
Last Evaluated: Dec 11, 2017
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 16:31091000
Last Evaluated: Dec 11, 2017
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 16:31091000
Last Evaluated: Dec 11, 2017
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 16:31091000
Last Evaluated: Dec 11, 2017
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 16:31091000
Expert Reviewed drug response
Hetero
Gene:
ERCC1
Variant:
c.354T>C
(p.Asn118=)
rsID: rs11615
Ref Allele: A
Alt Allele: G
Freq: 57.5449%
CADD: 1.504
ClinVar Submissions (2)
Last Evaluated: Dec 06, 2016
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:45420395
Xeroderma pigmentosum (XP) is characterized by: Sun sensitivity (severe sunburn with blistering, persistent erythema on minimal sun exposure in ~60% of affected individuals), with marked freckle-like pigmentation of the face before age two years in most affected individuals; Sunlight-induced ocular involvement (photophobia, keratitis, atrophy of the skin of the lids); Greatly increased risk of sunlight-induced cutaneous neoplasms (basal cell carcinoma, squamous cell carcinoma, melanoma). Approximately 25% of affected individuals have neurologic manifestations (acquired microcephaly, diminished or absent deep tendon stretch reflexes, progressive sensorineural hearing loss, and progressive cognitive impairment). The most common causes of death are skin cancer, neurologic degeneration, and internal cancer. The median age at death in persons with XP with neurodegeneration (29 years) was found to be younger than that in persons with XP without neurodegeneration (37 years).
Last Evaluated: Dec 06, 2016
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:45420395
Last Evaluated: Dec 06, 2016
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:45420395
Last Evaluated: Dec 06, 2016
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:45420395
Last Evaluated: Dec 06, 2016
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:45420395
Last Evaluated: Dec 06, 2016
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:45420395
Expert Reviewed drug response
Hetero
Gene:
MC4R
Variant:
g.60215554C>A
rsID: rs489693
Ref Allele: C
Alt Allele: A
Freq: 34.9667%
CADD: 0.12
ClinVar Submissions (1)
Last Evaluated: Jun 22, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 18:60215554
Last Evaluated: Jun 22, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 18:60215554
Clozapine is one of the most effective antipsychotics available in the treatment of schizophrenia and the only antipsychotic found to be effective in treatment-resistant schizophrenia. Clozapine is also used to reduce the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder. Compared to typical antipsychotics, clozapine is far less likely to cause movement disorders, known as extrapyramidal side effects, which include dystonia, akathisia, parkinsonism, and tardive dyskinesia. However, there are significant risks associated with clozapine therapy that limits its use to only the most severely ill patients who have not responded adequately to standard drug therapy. Most notably, because of the risk of clozapine-induced agranulocytosis, clozapine treatment requires monitoring of white blood counts and absolute neutrophil counts, and in the US, the FDA requires that patients receiving clozapine be enrolled in a computer-based registry. Clozapine is metabolized in the liver by the cytochrome P450 (CYP) system of enzymes. CYP1A2 is the main CYP isoform in clozapine metabolism and CYP1A2 activity is an important determinant of clozapine dose. Other CYP enzymes involved in clozapine metabolism include CYP2D6 and CYP3A4. Approximately 6-10% of Caucasians have reduced activity of CYP2D6 ("poor metabolizers"). These individuals may develop higher than expected plasma concentrations of clozapine with usual doses. The FDA-approved drug label for clozapine states that a dose reduction may be necessary in patients who are CYP2D6 poor metabolizers.
Last Evaluated: Jun 22, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 18:60215554
Last Evaluated: Jun 22, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 18:60215554
Last Evaluated: Jun 22, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 18:60215554
Last Evaluated: Jun 22, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 18:60215554
Last Evaluated: Jun 22, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 18:60215554
Last Evaluated: Jun 22, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 18:60215554
Last Evaluated: Jun 22, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 18:60215554
Expert Reviewed drug response
Hetero
Gene:
APOA5
Variant:
c.-644C>T
rsID: rs662799
Ref Allele: G
Alt Allele: A
Freq: 89.5929%
CADD: 3.29
ClinVar Submissions (1)
Last Evaluated: May 14, 2018
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 11:116792991
Last Evaluated: May 14, 2018
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 11:116792991
Last Evaluated: May 14, 2018
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 11:116792991
Insufficiently evaluated pharmacogenetic — associated with the triglyceride levels and the risk of first heart attack
Expert Reviewed drug response
Hetero
Gene:
DYNC2H1
Variant:
g.103547430A>G
rsID: rs716274
Ref Allele: A
Alt Allele: G
Freq: 49.5676%
CADD: 2.369
ClinVar Submissions (1)
Last Evaluated: Oct 14, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 11:103547430
Last Evaluated: Oct 14, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 11:103547430
Expert Reviewed drug response
Hetero
Gene:
SLC28A3
Variant:
c.862-360C>T
rsID: rs885004
Ref Allele: G
Alt Allele: A
Freq: 12.285%
CADD: 5.189
ClinVar Submissions (1)
Last Evaluated: Dec 20, 2017
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 9:84294635
Expert Reviewed drug response
Hetero
Gene:
UGT1A1
Variant:
c.-364C>T
rsID: rs887829
Ref Allele: C
Alt Allele: T
Freq: 34.8847%
CADD: 8.026
ClinVar Submissions (1)
Last Evaluated: Mar 23, 2018
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 2:233759924
Expert Reviewed drug response
Hetero
Gene:
LOC100996325
Variant:
n.366+1469G>A
rsID: rs924607
Ref Allele: C
Alt Allele: T
Freq: 30.6416%
CADD: 1.592
ClinVar Submissions (1)
Last Evaluated: Feb 23, 2017
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 5:609978
Expert Reviewed drug response
Hetero
Gene:
NAT2
Variant:
c.282C>T
(p.Tyr94=)
rsID: rs1041983
Ref Allele: C
Alt Allele: T
Freq: 36.3604%
CADD: 0.032
ClinVar Submissions (1)
Last Evaluated: Oct 27, 2017
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 8:18400285
Expert Reviewed drug response
Hetero
Gene:
TP53
Variant:
c.215C>G
(p.Pro72Arg)
rsID: rs1042522
Ref Allele: G
Alt Allele: C
Freq: 61.6654%
CADD: 6.813
ClinVar Submissions (15)
Last Evaluated: Aug 18, 2017
Review Status: reviewed by expert panel
Number of Submitters: 15
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 17:7676154
OMIM Allelic Variant: 191170.0005
Last Evaluated: Aug 18, 2017
Review Status: reviewed by expert panel
Number of Submitters: 15
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 17:7676154
OMIM Allelic Variant: 191170.0005
Last Evaluated: Aug 18, 2017
Review Status: reviewed by expert panel
Number of Submitters: 15
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 17:7676154
OMIM Allelic Variant: 191170.0005
Last Evaluated: Aug 18, 2017
Review Status: reviewed by expert panel
Number of Submitters: 15
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 17:7676154
OMIM Allelic Variant: 191170.0005
Last Evaluated: Aug 18, 2017
Review Status: reviewed by expert panel
Number of Submitters: 15
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 17:7676154
OMIM Allelic Variant: 191170.0005
Last Evaluated: Aug 18, 2017
Review Status: reviewed by expert panel
Number of Submitters: 15
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 17:7676154
OMIM Allelic Variant: 191170.0005
Last Evaluated: Aug 18, 2017
Review Status: reviewed by expert panel
Number of Submitters: 15
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 17:7676154
OMIM Allelic Variant: 191170.0005
Last Evaluated: Aug 18, 2017
Review Status: reviewed by expert panel
Number of Submitters: 15
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 17:7676154
OMIM Allelic Variant: 191170.0005
Last Evaluated: Aug 18, 2017
Review Status: reviewed by expert panel
Number of Submitters: 15
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 17:7676154
OMIM Allelic Variant: 191170.0005
Last Evaluated: Aug 18, 2017
Review Status: reviewed by expert panel
Number of Submitters: 15
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 17:7676154
OMIM Allelic Variant: 191170.0005
Last Evaluated: Aug 18, 2017
Review Status: reviewed by expert panel
Number of Submitters: 15
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 17:7676154
OMIM Allelic Variant: 191170.0005
Low clinical importance, Uncertain pathogenic — This is a common variant was first reported as a polymorphism. It has since had mixed associations with cancer: Storey et al. conclude a 7x *increased* risk of HPV cancer for homozygotes vs hets, but Jones et al. find a 1.98x *decreased* risk for colorectal cancer. This variant may have significant impact on particular cancers, but it is unclear what effect it has on the overall burden of cancer.
Expert Reviewed drug response
Hetero
Gene:
ADRB2
Variant:
c.46A=
(p.Arg16=)
rsID: rs1042713
Ref Allele: G
Alt Allele: A
Freq: 42.6104%
CADD: 16.81
ClinVar Submissions (1)
Last Evaluated: Oct 14, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 5:148826877
Last Evaluated: Oct 14, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 5:148826877
Expert Reviewed drug response
Hetero
Gene:
ABCB1
Variant:
c.3435T>C
(p.Ile1145=)
rsID: rs1045642
Ref Allele: A
Alt Allele: G
Freq: 59.2492%
CADD: 0.015
ClinVar Submissions (3)
Last Evaluated: Apr 24, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 7:87509329
OMIM Allelic Variant: 171050.0002
Last Evaluated: Apr 24, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 7:87509329
OMIM Allelic Variant: 171050.0002
Last Evaluated: Apr 24, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 7:87509329
OMIM Allelic Variant: 171050.0002
Last Evaluated: Apr 24, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 7:87509329
OMIM Allelic Variant: 171050.0002
Last Evaluated: Apr 24, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 7:87509329
OMIM Allelic Variant: 171050.0002
Last Evaluated: Apr 24, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 7:87509329
OMIM Allelic Variant: 171050.0002
Last Evaluated: Apr 24, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 7:87509329
OMIM Allelic Variant: 171050.0002
Last Evaluated: Apr 24, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 7:87509329
OMIM Allelic Variant: 171050.0002
Last Evaluated: Apr 24, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 7:87509329
OMIM Allelic Variant: 171050.0002
Last Evaluated: Apr 24, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 7:87509329
OMIM Allelic Variant: 171050.0002
Last Evaluated: Apr 24, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 7:87509329
OMIM Allelic Variant: 171050.0002
Last Evaluated: Apr 24, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 7:87509329
OMIM Allelic Variant: 171050.0002
Expert Reviewed drug response
Hetero
Gene:
CHRNA3
Variant:
c.645C>T
(p.Tyr215=)
rsID: rs1051730
Ref Allele: G
Alt Allele: A
Freq: 24.3932%
CADD: 22.5
ClinVar Submissions (2)
Last Evaluated: Apr 01, 2015
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 15:78601997
OMIM Allelic Variant: 118503.0001
Last Evaluated: Apr 01, 2015
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 15:78601997
OMIM Allelic Variant: 118503.0001
Last Evaluated: Apr 01, 2015
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 15:78601997
OMIM Allelic Variant: 118503.0001
Expert Reviewed drug response
Hetero
Gene:
CBR3
Variant:
c.730G>A
(p.Val244Met)
rsID: rs1056892
Ref Allele: G
Alt Allele: A
Freq: 39.35%
CADD: 18.79
ClinVar Submissions (1)
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 21:36146408
Expert Reviewed drug response
Homo
Gene:
ITPA
Variant:
c.94C>A
(p.Pro32Thr)
rsID: rs1127354
Ref Allele: C
Alt Allele: A
Freq: 6.5765%
CADD: 22.1
ClinVar Submissions (2)
Inosine triphosphate pyrophosphohydrolase (ITPase) deficiency is a common inherited condition characterized by the abnormal accumulation of inosine triphosphate (ITP) in erythrocytes (Sumi et al., 2002).
Last Evaluated: Aug 05, 2016
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 20:3213196
OMIM Allelic Variant: 147520.0001
Last Evaluated: Aug 05, 2016
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 20:3213196
OMIM Allelic Variant: 147520.0001
Last Evaluated: Aug 05, 2016
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 20:3213196
OMIM Allelic Variant: 147520.0001
Low clinical importance, pharmacogenetic — This variant is associated with inosine triphosphate pyrophosphohydrolase deficiency and may be associated with an adverse reaction to thiopurine drugs (which are used as immunosuppressants). Homozygotes have no detectable ITPase activity, individuals compound heterozygous with another less severe mutation also have severely reduced enzyme activity.
Expert Reviewed drug response
Hetero
Gene:
GATM
Variant:
c.-394-272A>G
rsID: rs1346268
Ref Allele: T
Alt Allele: C
Freq: 33.4942%
CADD: 5.676
ClinVar Submissions (1)
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 15:45380831
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 15:45380831
Expert Reviewed drug response
Hetero
Gene:
HTR2C
Variant:
c.551-3008C>G
rsID: rs1414334
Ref Allele: C
Alt Allele: G
Freq: 76.7066%
ClinVar Submissions (2)
Last Evaluated: Mar 09, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: X:114903581
Clozapine is one of the most effective antipsychotics available in the treatment of schizophrenia and the only antipsychotic found to be effective in treatment-resistant schizophrenia. Clozapine is also used to reduce the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder. Compared to typical antipsychotics, clozapine is far less likely to cause movement disorders, known as extrapyramidal side effects, which include dystonia, akathisia, parkinsonism, and tardive dyskinesia. However, there are significant risks associated with clozapine therapy that limits its use to only the most severely ill patients who have not responded adequately to standard drug therapy. Most notably, because of the risk of clozapine-induced agranulocytosis, clozapine treatment requires monitoring of white blood counts and absolute neutrophil counts, and in the US, the FDA requires that patients receiving clozapine be enrolled in a computer-based registry. Clozapine is metabolized in the liver by the cytochrome P450 (CYP) system of enzymes. CYP1A2 is the main CYP isoform in clozapine metabolism and CYP1A2 activity is an important determinant of clozapine dose. Other CYP enzymes involved in clozapine metabolism include CYP2D6 and CYP3A4. Approximately 6-10% of Caucasians have reduced activity of CYP2D6 ("poor metabolizers"). These individuals may develop higher than expected plasma concentrations of clozapine with usual doses. The FDA-approved drug label for clozapine states that a dose reduction may be necessary in patients who are CYP2D6 poor metabolizers.
Last Evaluated: Mar 09, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: X:114903581
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 09, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: X:114903581
Last Evaluated: Mar 09, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: X:114903581
Last Evaluated: Mar 09, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: X:114903581
Expert Reviewed drug response
Homo
Gene:
C8orf34
Variant:
c.736+8162C>G
rsID: rs1517114
Ref Allele: C
Alt Allele: G
Freq: 62.6147%
CADD: 0.335
ClinVar Submissions (1)
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 8:68476982
Expert Reviewed drug response
Hetero
Gene:
CETP
Variant:
c.658+186C>A
rsID: rs1532624
Ref Allele: C
Alt Allele: A
Freq: 33.2585%
CADD: 8.322
ClinVar Submissions (1)
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 16:56971567
Expert Reviewed drug response
Hetero
Gene:
-
Variant:
g.45328787C>T
rsID: rs1719247
Ref Allele: C
Alt Allele: T
Freq: 45.776%
CADD: 3.114
ClinVar Submissions (1)
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 15:45328787
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 15:45328787
Expert Reviewed drug response
Hetero
Gene:
ABCC4
Variant:
c.3348G>A
(p.Lys1116=)
rsID: rs1751034
Ref Allele: C
Alt Allele: T
Freq: 78.5089%
CADD: 7.895
ClinVar Submissions (1)
Last Evaluated: May 15, 2017
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 13:95062722
Expert Reviewed drug response
Homo
Gene:
NAT2
Variant:
c.590G>A
(p.Arg197Gln)
rsID: rs1799930
Ref Allele: G
Alt Allele: A
Freq: 27.0889%
CADD: 18.73
ClinVar Submissions (2)
Last Evaluated: Oct 27, 2017
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 8:18400593
OMIM Allelic Variant: 612182.0001
Last Evaluated: Oct 27, 2017
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 8:18400593
OMIM Allelic Variant: 612182.0001
Insufficiently evaluated pharmacogenetic — This allele characterizes the NAT2*6A haplotype which causes slow acetylation.
Expert Reviewed drug response
Hetero
Gene:
FCGR2A
Variant:
c.497A>G
(p.His166Arg)
rsID: rs1801274
Ref Allele: A
Alt Allele: G
Freq: 50.5431%
CADD: 0.08
ClinVar Submissions (3)
Last Evaluated: Mar 28, 2016
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 1:161509955
OMIM Allelic Variant: 146790.0001
Last Evaluated: Mar 28, 2016
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 1:161509955
OMIM Allelic Variant: 146790.0001
Last Evaluated: Mar 28, 2016
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 1:161509955
OMIM Allelic Variant: 146790.0001
Last Evaluated: Mar 28, 2016
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 1:161509955
OMIM Allelic Variant: 146790.0001
Last Evaluated: Mar 28, 2016
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 1:161509955
OMIM Allelic Variant: 146790.0001
Expert Reviewed drug response
Hetero
Gene:
MTRR
Variant:
c.66A>G
(p.Ile22Met)
rsID: rs1801394
Ref Allele: A
Alt Allele: G
Freq: 43.3765%
CADD: 20.7
ClinVar Submissions (6)
Last Evaluated: Jan 30, 2018
Review Status: reviewed by expert panel
Number of Submitters: 6
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 5:7870860
OMIM Allelic Variant: 602568.0003
Last Evaluated: Jan 30, 2018
Review Status: reviewed by expert panel
Number of Submitters: 6
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 5:7870860
OMIM Allelic Variant: 602568.0003
Last Evaluated: Jan 30, 2018
Review Status: reviewed by expert panel
Number of Submitters: 6
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 5:7870860
OMIM Allelic Variant: 602568.0003
Last Evaluated: Jan 30, 2018
Review Status: reviewed by expert panel
Number of Submitters: 6
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 5:7870860
OMIM Allelic Variant: 602568.0003
Last Evaluated: Jan 30, 2018
Review Status: reviewed by expert panel
Number of Submitters: 6
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 5:7870860
OMIM Allelic Variant: 602568.0003
Last Evaluated: Jan 30, 2018
Review Status: reviewed by expert panel
Number of Submitters: 6
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 5:7870860
OMIM Allelic Variant: 602568.0003
Low clinical importance, Likely pathogenic — This common variant (HapMap allele frequency of 31.3%) in a protein involved in folate (B9) and cobalamin (B12) metabolism and is often reported as "MTRR I22M" (an alternative transcript position). Mothers homozygous for this variant are associated with having around a increased chance of a child with Down syndrome (risk of 0.4%, average risk in population is 0.25%). Notably, age plays a far larger role in the rate of Down syndrome (risk is 4.5% for a mother 45-years-of-age), and it is unknown how this variant may combine with the effect of age. There are conflicting reports associating this variant with incidence of neural tube defects, possibly when combined with MTHFR A222V.
Expert Reviewed drug response
Hetero
Gene:
CRHR1
Variant:
c.1194+111C>T
rsID: rs1876828
Ref Allele: C
Alt Allele: T
Freq: 14.7992%
CADD: 6.162
ClinVar Submissions (1)
Last Evaluated: Apr 07, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 17:45834159
Last Evaluated: Apr 07, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 17:45834159
Last Evaluated: Apr 07, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 17:45834159
Last Evaluated: Apr 07, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 17:45834159
Last Evaluated: Apr 07, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 17:45834159
Expert Reviewed drug response
Hetero
Gene:
TMEM43;XPC
Variant:
c.2815C>A
(p.Gln939Lys)
rsID: rs2228001
Ref Allele: G
Alt Allele: T
Freq: 64.307%
CADD: 14.73
ClinVar Submissions (4)
Arrhythmogenic right ventricular cardiomyopathy (ARVC) – previously referred to as arrhythmogenic right ventricular dysplasia (ARVD) – is characterized by progressive fibrofatty replacement of the myocardium that predisposes to ventricular tachycardia and sudden death in young individuals and athletes. It primarily affects the right ventricle, and it may also involve the left ventricle. The presentation of disease is highly variable even within families, and some affected individuals may not meet established clinical criteria. The mean age at diagnosis is 31 years (±13; range: 4-64 years).
Last Evaluated: May 03, 2017
Review Status: reviewed by expert panel
Number of Submitters: 4
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 3:14145949
Xeroderma pigmentosum (XP) is characterized by: Sun sensitivity (severe sunburn with blistering, persistent erythema on minimal sun exposure in ~60% of affected individuals), with marked freckle-like pigmentation of the face before age two years in most affected individuals; Sunlight-induced ocular involvement (photophobia, keratitis, atrophy of the skin of the lids); Greatly increased risk of sunlight-induced cutaneous neoplasms (basal cell carcinoma, squamous cell carcinoma, melanoma). Approximately 25% of affected individuals have neurologic manifestations (acquired microcephaly, diminished or absent deep tendon stretch reflexes, progressive sensorineural hearing loss, and progressive cognitive impairment). The most common causes of death are skin cancer, neurologic degeneration, and internal cancer. The median age at death in persons with XP with neurodegeneration (29 years) was found to be younger than that in persons with XP without neurodegeneration (37 years).
Last Evaluated: May 03, 2017
Review Status: reviewed by expert panel
Number of Submitters: 4
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 3:14145949
Last Evaluated: May 03, 2017
Review Status: reviewed by expert panel
Number of Submitters: 4
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 3:14145949
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: May 03, 2017
Review Status: reviewed by expert panel
Number of Submitters: 4
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 3:14145949
Expert Reviewed drug response
Hetero
Gene:
VDR
Variant:
c.2T>C
(p.Met1Thr)
rsID: rs2228570
Ref Allele: A
Alt Allele: G
Freq: 65.9746%
CADD: 24.6
ClinVar Submissions (3)
Last Evaluated: Mar 01, 2017
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 12:47879112
Last Evaluated: Mar 01, 2017
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 12:47879112
Last Evaluated: Mar 01, 2017
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 12:47879112
Expert Reviewed drug response
Homo
Gene:
HAS3
Variant:
c.279A>G
(p.Ala93=)
rsID: rs2232228
Ref Allele: A
Alt Allele: G
Freq: 33.7801%
CADD: 13.71
ClinVar Submissions (1)
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 16:69109674
Expert Reviewed drug response
Hetero
Gene:
EPHX1
Variant:
c.416A>G
(p.His139Arg)
rsID: rs2234922
Ref Allele: A
Alt Allele: G
Freq: 22.966%
CADD: 7.774
ClinVar Submissions (2)
Last Evaluated: Jan 20, 2016
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 1:225838705
OMIM Allelic Variant: 132810.0002
Last Evaluated: Jan 20, 2016
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 1:225838705
OMIM Allelic Variant: 132810.0002
Expert Reviewed drug response
Hetero
Gene:
CYP2B6
Variant:
c.823-197T>C
rsID: rs2279345
Ref Allele: T
Alt Allele: C
Freq: 67.6653%
CADD: 1.711
ClinVar Submissions (1)
Last Evaluated: Dec 20, 2017
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:41009797
Expert Reviewed drug response
Homo
Gene:
ADORA2A
Variant:
c.-275+1797C>T
rsID: rs2298383
Ref Allele: C
Alt Allele: T
Freq: 47.8283%
CADD: 0.205
ClinVar Submissions (1)
Last Evaluated: Dec 20, 2017
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 22:24429543
Expert Reviewed drug response
Homo
Gene:
VKORC1
Variant:
c.283+837T>C
rsID: rs2359612
Ref Allele: A
Alt Allele: G
Freq: 62.7994%
CADD: 0.93
ClinVar Submissions (1)
Last Evaluated: Dec 07, 2017
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 16:31092475
Expert Reviewed drug response
Hetero
Gene:
CYP3A4
Variant:
c.-392G>A
rsID: rs2740574
Ref Allele: C
Alt Allele: T
Freq: 77.7308%
CADD: 3.399
ClinVar Submissions (2)
Last Evaluated: Feb 23, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 7:99784473
OMIM Allelic Variant: 124010.0001
Last Evaluated: Feb 23, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 7:99784473
OMIM Allelic Variant: 124010.0001
Last Evaluated: Feb 23, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 7:99784473
OMIM Allelic Variant: 124010.0001
Expert Reviewed drug response
Homo
Gene:
VKORC1
Variant:
c.173+324T>G
rsID: rs2884737
Ref Allele: A
Alt Allele: C
Freq: 16.7232%
CADD: 3.96
ClinVar Submissions (1)
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 16:31094233
Expert Reviewed drug response
Hetero
Gene:
-
Variant:
g.207629510T>C
rsID: rs2952768
Ref Allele: T
Alt Allele: C
Freq: 34.9683%
CADD: 6.283
ClinVar Submissions (1)
Last Evaluated: Oct 14, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 2:207629510
Last Evaluated: Oct 14, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 2:207629510
Last Evaluated: Oct 14, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 2:207629510
Last Evaluated: Oct 14, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 2:207629510
Last Evaluated: Oct 14, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 2:207629510
Last Evaluated: Oct 14, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 2:207629510
Expert Reviewed drug response
Homo
Gene:
ERCC1
Variant:
c.*197G>T
rsID: rs3212986
Ref Allele: C
Alt Allele: A
Freq: 27.718%
CADD: 0.61
ClinVar Submissions (1)
Last Evaluated: Jun 27, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:45409478
Last Evaluated: Jun 27, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:45409478
Last Evaluated: Jun 27, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:45409478
Expert Reviewed drug response
Hetero
Gene:
PTGFR
Variant:
c.-562T>C
rsID: rs3753380
Ref Allele: T
Alt Allele: C
Freq: 78.9891%
CADD: 6.726
ClinVar Submissions (1)
Last Evaluated: Jan 21, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 1:78490747
Expert Reviewed drug response
Hetero
Gene:
SCN1A
Variant:
c.603-91G>A
rsID: rs3812718
Ref Allele: C
Alt Allele: T
Freq: 47.6706%
CADD: 18.66
ClinVar Submissions (2)
Last Evaluated: Nov 23, 2017
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 2:166053034
OMIM Allelic Variant: 182389.0016
Last Evaluated: Nov 23, 2017
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 2:166053034
OMIM Allelic Variant: 182389.0016
Last Evaluated: Nov 23, 2017
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 2:166053034
OMIM Allelic Variant: 182389.0016
Last Evaluated: Nov 23, 2017
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 2:166053034
OMIM Allelic Variant: 182389.0016
Last Evaluated: Nov 23, 2017
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 2:166053034
OMIM Allelic Variant: 182389.0016
Expert Reviewed drug response
Hetero
Gene:
CYP2D6
Variant:
c.506-1G>A
rsID: rs3892097
Ref Allele: C
Alt Allele: T
Freq: 14.4894%
CADD: 27.4
ClinVar Submissions (4)
Last Evaluated: Aug 06, 2018
Review Status: reviewed by expert panel
Number of Submitters: 4
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 22:42128945
OMIM Allelic Variant: 124030.0001
Last Evaluated: Aug 06, 2018
Review Status: reviewed by expert panel
Number of Submitters: 4
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 22:42128945
OMIM Allelic Variant: 124030.0001
Last Evaluated: Aug 06, 2018
Review Status: reviewed by expert panel
Number of Submitters: 4
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 22:42128945
OMIM Allelic Variant: 124030.0001
Last Evaluated: Aug 06, 2018
Review Status: reviewed by expert panel
Number of Submitters: 4
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 22:42128945
OMIM Allelic Variant: 124030.0001
Last Evaluated: Aug 06, 2018
Review Status: reviewed by expert panel
Number of Submitters: 4
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 22:42128945
OMIM Allelic Variant: 124030.0001
Last Evaluated: Aug 06, 2018
Review Status: reviewed by expert panel
Number of Submitters: 4
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 22:42128945
OMIM Allelic Variant: 124030.0001
Last Evaluated: Aug 06, 2018
Review Status: reviewed by expert panel
Number of Submitters: 4
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 22:42128945
OMIM Allelic Variant: 124030.0001
Last Evaluated: Aug 06, 2018
Review Status: reviewed by expert panel
Number of Submitters: 4
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 22:42128945
OMIM Allelic Variant: 124030.0001
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Aug 06, 2018
Review Status: reviewed by expert panel
Number of Submitters: 4
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 22:42128945
OMIM Allelic Variant: 124030.0001
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 06, 2018
Review Status: reviewed by expert panel
Number of Submitters: 4
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 22:42128945
OMIM Allelic Variant: 124030.0001
Last Evaluated: Aug 06, 2018
Review Status: reviewed by expert panel
Number of Submitters: 4
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 22:42128945
OMIM Allelic Variant: 124030.0001
Last Evaluated: Aug 06, 2018
Review Status: reviewed by expert panel
Number of Submitters: 4
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 22:42128945
OMIM Allelic Variant: 124030.0001
Expert Reviewed drug response
Hetero
Gene:
CYP2C19
Variant:
c.681G>A
(p.Pro227=)
rsID: rs4244285
Ref Allele: G
Alt Allele: A
Freq: 16.7312%
CADD: 2.285
ClinVar Submissions (4)
Clopidogrel is a thienopyridine antiplatelet agent that prevents platelet activation and aggregation by irreversibly inhibiting the P2Y12 ADP receptors. As a pro-drug, clopidogrel requires hepatic biotransformation to form an active metabolite. This conversion is composed of two sequential oxidative steps, which involve cytochrome P450-2C19 (CYP2C19) and other enzymes. Genetic variants in CYP2C19 such as CYP2C19*2, along with other genetic and non-genetic factors, are known to influence variability in clopidogrel response. Specific CYP2C19 variants impair formation of the active clopidogrel metabolite, which results in reduced platelet inhibition. Among clopidogrel-treated patients with acute coronary syndromes (ACSs) undergoing percutaneous coronary intervention (PCI), patients with specific variants in the CYP2C19 gene might be at increased risk for serious adverse cardiovascular events and may benefit from an alternative antiplatelet therapy as compared to patients without these variants. Guidelines regarding the use of pharmacogenomic tests in dosing for clopidogrel have been published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and are available on the PharmGKB website.
Last Evaluated: Aug 07, 2018
Review Status: reviewed by expert panel
Number of Submitters: 4
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 10:94781859
OMIM Allelic Variant: 124020.0001
Last Evaluated: Aug 07, 2018
Review Status: reviewed by expert panel
Number of Submitters: 4
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 10:94781859
OMIM Allelic Variant: 124020.0001
Last Evaluated: Aug 07, 2018
Review Status: reviewed by expert panel
Number of Submitters: 4
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 10:94781859
OMIM Allelic Variant: 124020.0001
Last Evaluated: Aug 07, 2018
Review Status: reviewed by expert panel
Number of Submitters: 4
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 10:94781859
OMIM Allelic Variant: 124020.0001
Last Evaluated: Aug 07, 2018
Review Status: reviewed by expert panel
Number of Submitters: 4
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 10:94781859
OMIM Allelic Variant: 124020.0001
Last Evaluated: Aug 07, 2018
Review Status: reviewed by expert panel
Number of Submitters: 4
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 10:94781859
OMIM Allelic Variant: 124020.0001
Last Evaluated: Aug 07, 2018
Review Status: reviewed by expert panel
Number of Submitters: 4
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 10:94781859
OMIM Allelic Variant: 124020.0001
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Aug 07, 2018
Review Status: reviewed by expert panel
Number of Submitters: 4
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 10:94781859
OMIM Allelic Variant: 124020.0001
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 07, 2018
Review Status: reviewed by expert panel
Number of Submitters: 4
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 10:94781859
OMIM Allelic Variant: 124020.0001
Insufficiently evaluated pharmacogenetic — This variant defines the CYP2C19*2 haplotype and is associated with diminished response of clopidogrel (plavix). Compared to individuals who do not have this variant, carriers of this variant are more likely to have a major adverse cardiovascular event despite treatment with clopidogrel.
Expert Reviewed drug response
Hetero
Gene:
EGF
Variant:
c.-382A>G
rsID: rs4444903
Ref Allele: A
Alt Allele: G
Freq: 52.4321%
CADD: 8.542
ClinVar Submissions (2)
Last Evaluated: Feb 01, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 4:109912954
Last Evaluated: Feb 01, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 4:109912954
Expert Reviewed drug response
Hetero
Gene:
ATIC
Variant:
c.1503+675T>C
rsID: rs4673993
Ref Allele: T
Alt Allele: C
Freq: 26.3801%
CADD: 1.942
ClinVar Submissions (1)
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 2:215347616
Expert Reviewed drug response
Homo
Gene:
COQ2
Variant:
c.779-1022C>G
rsID: rs4693075
Ref Allele: G
Alt Allele: C
Freq: 61.6184%
CADD: 1.96
ClinVar Submissions (1)
Last Evaluated: Oct 14, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 4:83271015
Last Evaluated: Oct 14, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 4:83271015
Last Evaluated: Oct 14, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 4:83271015
Expert Reviewed drug response
Hetero
Gene:
FKBP5
Variant:
c.-20+18122T>C
rsID: rs4713916
Ref Allele: A
Alt Allele: G
Freq: 77.1709%
CADD: 0.798
ClinVar Submissions (1)
Last Evaluated: Oct 14, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 6:35702206
Last Evaluated: Oct 14, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 6:35702206
Last Evaluated: Oct 14, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 6:35702206
Last Evaluated: Oct 14, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 6:35702206
Last Evaluated: Oct 14, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 6:35702206
Last Evaluated: Oct 14, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 6:35702206
Last Evaluated: Oct 14, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 6:35702206
Expert Reviewed drug response
Homo
Gene:
CYP2B6
Variant:
c.485-18C>T
rsID: rs4803419
Ref Allele: C
Alt Allele: T
Freq: 26.6628%
CADD: 2.548
ClinVar Submissions (1)
Last Evaluated: Dec 11, 2017
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:41006887
Expert Reviewed drug response
Homo
Gene:
DPP6
Variant:
c.52-71279T>C
rsID: rs6977820
Ref Allele: T
Alt Allele: C
Freq: 58.4257%
CADD: 6.496
ClinVar Submissions (1)
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 7:154374935
Expert Reviewed drug response
Homo
Gene:
COL22A1
Variant:
c.658+5484G>A
rsID: rs6988229
Ref Allele: C
Alt Allele: T
Freq: 28.207%
CADD: 0.375
ClinVar Submissions (1)
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 8:138872266
Expert Reviewed drug response
Hetero
Gene:
VKORC1
Variant:
g.296C>T
rsID: rs7196161
Ref Allele: G
Alt Allele: A
Freq: 55.4918%
CADD: 1.773
ClinVar Submissions (1)
Last Evaluated: Dec 11, 2017
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 16:31099660
Expert Reviewed drug response
Homo
Gene:
SEMA3C
Variant:
c.103+13883A>G
rsID: rs7779029
Ref Allele: T
Alt Allele: C
Freq: 14.9521%
CADD: 0.448
ClinVar Submissions (1)
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 7:80902796
Expert Reviewed drug response
Hetero
Gene:
SLC28A3
Variant:
c.1381C>T
(p.Leu461=)
rsID: rs7853758
Ref Allele: G
Alt Allele: A
Freq: 19.716%
CADD: 17.57
ClinVar Submissions (1)
Last Evaluated: Dec 20, 2017
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 9:84286011
Expert Reviewed drug response
Hetero
Gene:
TCF7L2
Variant:
c.382-41435C>T
rsID: rs7903146
Ref Allele: C
Alt Allele: T
Freq: 27.0921%
CADD: 3.637
ClinVar Submissions (2)
Type 2 diabetes is a disorder characterized by abnormally high blood sugar levels. In this form of diabetes, the body stops using and making insulin properly. Insulin is a hormone produced in the pancreas that helps regulate blood sugar levels. Specifically, insulin controls how much glucose (a type of sugar) is passed from the blood into cells, where it is used as an energy source. When blood sugar levels are high (such as after a meal), the pancreas releases insulin to move the excess glucose into cells, which reduces the amount of glucose in the blood.Most people who develop type 2 diabetes first have insulin resistance, a condition in which the body's cells use insulin less efficiently than normal. As insulin resistance develops, more and more insulin is needed to keep blood sugar levels in the normal range. To keep up with the increasing need, insulin-producing cells in the pancreas (called beta cells) make larger amounts of insulin. Over time, the beta cells become less able to respond to blood sugar changes, leading to an insulin shortage that prevents the body from reducing blood sugar levels effectively. Most people have some insulin resistance as they age, but inadequate exercise and excessive weight gain make it worse, greatly increasing the likelihood of developing type 2 diabetes.Type 2 diabetes can occur at any age, but it most commonly begins in middle age or later. Signs and symptoms develop slowly over years. They include frequent urination (polyuria), excessive thirst (polydipsia), fatigue, blurred vision, tingling or loss of feeling in the hands and feet (diabetic neuropathy), sores that do not heal well, and weight loss. If blood sugar levels are not controlled through medication or diet, type 2 diabetes can cause long-lasting (chronic) health problems including heart disease and stroke; nerve damage; and damage to the kidneys, eyes, and other parts of the body.
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 10:112998590
OMIM Allelic Variant: 602228.0001
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 10:112998590
OMIM Allelic Variant: 602228.0001
Insufficiently evaluated pathogenic — associated with colorectal cancer for the T allele.
Expert Reviewed drug response
Hetero
Gene:
HTR2A
Variant:
c.614-2211T>C
rsID: rs7997012
Ref Allele: A
Alt Allele: G
Freq: 71.3279%
CADD: 11.64
ClinVar Submissions (3)
Last Evaluated: Mar 09, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 13:46837850
OMIM Allelic Variant: 182135.0003
Last Evaluated: Mar 09, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 13:46837850
OMIM Allelic Variant: 182135.0003
Last Evaluated: Mar 09, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 13:46837850
OMIM Allelic Variant: 182135.0003
Last Evaluated: Mar 09, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 13:46837850
OMIM Allelic Variant: 182135.0003
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 09, 2018
Review Status: reviewed by expert panel
Number of Submitters: 3
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 13:46837850
OMIM Allelic Variant: 182135.0003
Expert Reviewed drug response
Hetero
Gene:
VKORC1
Variant:
c.283+124G>C
rsID: rs8050894
Ref Allele: C
Alt Allele: G
Freq: 39.1159%
CADD: 1.82
ClinVar Submissions (2)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 09, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 16:31093188
Last Evaluated: Mar 09, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 16:31093188
Expert Reviewed drug response
Hetero
Gene:
IFNL3
Variant:
g.39252525T>G
rsID: rs8099917
Ref Allele: T
Alt Allele: G
Freq: 15.2539%
CADD: 15.16
ClinVar Submissions (1)
Last Evaluated: Oct 16, 2017
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:39252525
Last Evaluated: Oct 16, 2017
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:39252525
Expert Reviewed drug response
Homo
Gene:
VKORC1
Variant:
c.174-136C>T
rsID: rs9934438
Ref Allele: G
Alt Allele: A
Freq: 33.6352%
CADD: 14.98
ClinVar Submissions (5)
Last Evaluated: Apr 05, 2018
Review Status: reviewed by expert panel
Number of Submitters: 5
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 16:31093557
OMIM Allelic Variant: 608547.0008
Warfarin is an oral anti-coagulant used world-wide to treat and prevent thrombotic disorders. While it is highly effective, it has a very narrow therapeutic index making it difficult to dose correctly. Genetic variants in both cytochrome P450-2C9 (CYP2C9) and vitamin K-epoxide reductase complex (VKORC1) enzymes, along with non-genetic factors, are known to affect warfarin dose variability. Patients with specific variants in the gene CYP2C9 (the primary warfarin-metabolizing enzyme), such as CYP2C9*2 and CYP2C9*3, may require a lower dose of warfarin as compared to patients without these variants. Patients with a specific variant in VKORC1 (the target enzyme of warfarin), known as -1639G>A or rs9923231, may require a lower warfarin dose as compared to patients who do not have this variant. The combination of CYP2C9 and VKORC1 genetic variants, along with clinical factors, can put some patients at risk for adverse events such as bleeding. Guidelines regarding the use of pharmacogenomic tests in dosing for warfarin have been published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and are available on the PharmGKB website.
Last Evaluated: Apr 05, 2018
Review Status: reviewed by expert panel
Number of Submitters: 5
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 16:31093557
OMIM Allelic Variant: 608547.0008
Last Evaluated: Apr 05, 2018
Review Status: reviewed by expert panel
Number of Submitters: 5
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 16:31093557
OMIM Allelic Variant: 608547.0008
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Apr 05, 2018
Review Status: reviewed by expert panel
Number of Submitters: 5
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 16:31093557
OMIM Allelic Variant: 608547.0008
Last Evaluated: Apr 05, 2018
Review Status: reviewed by expert panel
Number of Submitters: 5
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 16:31093557
OMIM Allelic Variant: 608547.0008
Last Evaluated: Apr 05, 2018
Review Status: reviewed by expert panel
Number of Submitters: 5
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 16:31093557
OMIM Allelic Variant: 608547.0008
Insufficiently evaluated pharmacogenetic — gene VKORC1 SNP 1173 C>T is strongly associated with low warfarin dose requirement.
Expert Reviewed drug response
Hetero
Gene:
C11orf65
Variant:
c.175-5285G>T
rsID: rs11212617
Ref Allele: C
Alt Allele: A
Freq: 47.0924%
CADD: 2.33
ClinVar Submissions (1)
Last Evaluated: Nov 17, 2017
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 11:108412434
Expert Reviewed drug response
Hetero
Gene:
IFNL3
Variant:
c.259-126T>C
rsID: rs11881222
Ref Allele: A
Alt Allele: G
Freq: 29.6994%
CADD: 4.956
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:39244283
Last Evaluated: Jun 14, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:39244283
Last Evaluated: Jun 14, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:39244283
Expert Reviewed drug response
Homo
Gene:
-
Variant:
g.94645745G>A
rsID: rs12777823
Ref Allele: G
Alt Allele: A
Freq: 19.157%
CADD: 1.903
ClinVar Submissions (1)
Last Evaluated: Mar 09, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 10:94645745
Expert Reviewed drug response
Hetero
Gene:
IFNL3;IFNL4
Variant:
c.151-152G>A
rsID: rs12979860
Ref Allele: C
Alt Allele: T
Freq: 39.0673%
CADD: 1.703
ClinVar Submissions (2)
Last Evaluated: Apr 05, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:39248147
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Apr 05, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:39248147
Last Evaluated: Apr 05, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:39248147
Last Evaluated: Apr 05, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:39248147
Last Evaluated: Apr 05, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:39248147
Last Evaluated: Apr 05, 2018
Review Status: reviewed by expert panel
Number of Submitters: 2
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 19:39248147
Expert Reviewed drug response
Homo
Gene:
PRKCA
Variant:
c.1854+3730G>A
rsID: rs16960228
Ref Allele: G
Alt Allele: A
Freq: 14.2218%
CADD: 0.139
ClinVar Submissions (1)
Last Evaluated: Jul 11, 2016
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 17:66792709
Expert Reviewed drug response
Hetero
Gene:
MC4R
Variant:
g.60183864T>C
rsID: rs17782313
Ref Allele: T
Alt Allele: C
Freq: 24.1128%
CADD: 3.5
ClinVar Submissions (1)
Last Evaluated: Sep 22, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 18:60183864
Expert Reviewed drug response
Hetero
Below are mutations from ClinVar that were submitted as "clinically significant." Variants shown may or may not be truly clinically significant. The data presented has no guarantees of reporting accuracy. Heterozygous variants are reported as yellow and homozygous variants as red. A red or yellow variant does not necessarily mean one has or carries a condition or disease. This is for research and educational purposes only.
Gene:
SCN1A
Variant:
c.4793A>T
(p.Tyr1598Phe)
rsID: rs377325221
Ref Allele: T
Alt Allele: A
Freq: 0.0016%rare
CADD: 27.8
ClinVar Submissions (3)
Last Evaluated: Aug 24, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:165994205
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Aug 24, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:165994205
Clinically Significant Conflicting/Uncertain
Hetero
Gene:
ACY1
Variant:
c.841C>T
(p.Arg281Cys)
rsID: rs121912698
Ref Allele: C
Alt Allele: T
Freq: 0.274%rare
CADD: 23.9
ClinVar Submissions (4)
Aminoacylase-1 deficiency (ACY1D) is a rare autosomal recessive inborn error of metabolism characterized by increased urinary excretion of specific N-actyl amino acids. Most patients show neurologic abnormalities such as intellectual disability, seizures, hypotonia, and motor delay (summary by Ferri et al., 2014).
Last Evaluated: Dec 03, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:51988821
OMIM Allelic Variant: 104620.0002
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Dec 03, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:51988821
OMIM Allelic Variant: 104620.0002
Clinically Significant Conflicting/Uncertain
Hetero
Gene:
GLI3
Variant:
c.2179G>A
(p.Gly727Arg)
rsID: rs121917710
Ref Allele: C
Alt Allele: T
Freq: 0.4269%rare
CADD: 26.1
ClinVar Submissions (7)
Typical Greig cephalopolysyndactyly syndrome (GCPS) is characterized by preaxial polydactyly or mixed pre- and postaxial polydactyly, true widely spaced eyes, and macrocephaly. Individuals with mild GCPS may have subtle craniofacial findings. The mild end of the GCPS spectrum is a continuum with preaxial polysyndactyly type IV and crossed polydactyly (preaxial polydactyly of the feet and postaxial polydactyly of the hands plus syndactyly of fingers 3-4 and toes 1-3). Individuals with severe GCPS can have seizures, hydrocephalus, and intellectual disability.
Last Evaluated: May 03, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 7:41967848
OMIM Allelic Variant: 165240.0009
Typical Greig cephalopolysyndactyly syndrome (GCPS) is characterized by preaxial polydactyly or mixed pre- and postaxial polydactyly, true widely spaced eyes, and macrocephaly. Individuals with mild GCPS may have subtle craniofacial findings. The mild end of the GCPS spectrum is a continuum with preaxial polysyndactyly type IV and crossed polydactyly (preaxial polydactyly of the feet and postaxial polydactyly of the hands plus syndactyly of fingers 3-4 and toes 1-3). Individuals with severe GCPS can have seizures, hydrocephalus, and intellectual disability.
Last Evaluated: May 03, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 7:41967848
OMIM Allelic Variant: 165240.0009
Pallister-Hall syndrome (referred to as PHS in this entry) is characterized by a spectrum of anomalies ranging from polydactyly, asymptomatic bifid epiglottis, and hypothalamic hamartoma at the mild end to laryngotracheal cleft with neonatal lethality at the severe end. Individuals with mild PHS may be incorrectly diagnosed as having isolated postaxial polydactyly type A. Individuals with PHS can have pituitary insufficiency and may die as neonates from undiagnosed and untreated adrenal insufficiency.
Last Evaluated: May 03, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 7:41967848
OMIM Allelic Variant: 165240.0009
Pallister-Hall syndrome (referred to as PHS in this entry) is characterized by a spectrum of anomalies ranging from polydactyly, asymptomatic bifid epiglottis, and hypothalamic hamartoma at the mild end to laryngotracheal cleft with neonatal lethality at the severe end. Individuals with mild PHS may be incorrectly diagnosed as having isolated postaxial polydactyly type A. Individuals with PHS can have pituitary insufficiency and may die as neonates from undiagnosed and untreated adrenal insufficiency.
Last Evaluated: May 03, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 7:41967848
OMIM Allelic Variant: 165240.0009
A congenital abnormality characterized by more than 5 digits on a hand or foot.
Last Evaluated: May 03, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 7:41967848
OMIM Allelic Variant: 165240.0009
Polydactyly refers to the occurrence of supernumerary digits and is the most frequent of congenital hand and foot deformities. Based on the location of the extra digits, polydactyly can be classified into preaxial, involving the thumb or great toe; postaxial, affecting the fifth digit; and central, involving the 3 central digits. Postaxial polydactyly (PAP) is further subclassified into 2 types: in type A, a well-formed extra digit articulates with the fifth or a sixth metacarpal, whereas in type B, a rudimentary, poorly developed extra digit is present (summary by Umm-e-Kalsoom et al., 2012). Genetic Heterogeneity of Postaxial Polydactyly Other forms of postaxial polydactyly type A include PAPA2 (602085) on chromosome 13q21; PAPA3 (607324) on chromosome 19p13; PAPA4 (608562) on chromosome 7q22; PAPA5 (263450) on chromosome 13q13; PAPA6 (615226), caused by mutation in the ZNF141 gene (194648) on chromosome 4p16; PAPA7 (617642), caused by mutation in the IQCE gene (617631) on chromosome 7p22; and PAPA8 (618123), caused by mutation in the GLI1 gene (165220) on chromosome 12q13.
Last Evaluated: May 03, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 7:41967848
OMIM Allelic Variant: 165240.0009
Last Evaluated: May 03, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 7:41967848
OMIM Allelic Variant: 165240.0009
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: May 03, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 7:41967848
OMIM Allelic Variant: 165240.0009
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: May 03, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 7:41967848
OMIM Allelic Variant: 165240.0009
Low clinical importance, Uncertain pathogenic — Reported to cause postaxial polydactyly in a dominant manner. However it was only observed in one family, another linked variant in the region may have been causal. Data in the exome variant server shows 1 in 100 carry this variant, contracting the polydactyly effect -- if that hypothesis were true, this variant is common enough that it would account for a large fraction of cases (i.e. many other publications would exist confirming the hypothesis). Other variants in this gene cause Pallister-Hall syndrome, which causes many traits including polydactyly and hypothalamic hamartoma (a congenital brain malformation that can cause seizures).
Clinically Significant Conflicting/Uncertain
Hetero
Gene:
SLC4A1
Variant:
c.118G>A
(p.Glu40Lys)
rsID: rs45562031
Ref Allele: C
Alt Allele: T
Freq: 1.2304%uncommon
CADD: 11.61
ClinVar Submissions (6)
A condition of inadequate circulating red blood cells (ANEMIA) or insufficient HEMOGLOBIN due to premature destruction of red blood cells (ERYTHROCYTES).
Last Evaluated: Dec 15, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 17:44261625
OMIM Allelic Variant: 109270.0004
Cryohydrocytosis is an exceedingly rare condition characterized by a mild stomatocytic hemolytic state with hyperbilirubinemia. A hallmark of this condition is that red blood cells (RBCs) lyse on storage at 4 degrees centigrade. RBC cation permeability is increased at 37 degrees centigrade, and the cells also accumulate sodium in the cold (summary by Coles et al., 1999). Patients present with fatigue, mild anemia, and pseudohyperkalemia due to a potassium leak from the RBCs (summary by Bogdanova et al., 2010). For a discussion of clinical and genetic heterogeneity of the hereditary stomatocytoses, see 194380.
Last Evaluated: Dec 15, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 17:44261625
OMIM Allelic Variant: 109270.0004
Hereditary spherocytosis is a condition that affects red blood cells. People with this condition typically experience a shortage of red blood cells (anemia), yellowing of the eyes and skin (jaundice), and an enlarged spleen (splenomegaly). Most newborns with hereditary spherocytosis have severe anemia, although it improves after the first year of life. Splenomegaly can occur anytime from early childhood to adulthood. About half of affected individuals develop hard deposits in the gallbladder called gallstones, which typically occur from late childhood to mid-adulthood.There are four forms of hereditary spherocytosis, which are distinguished by the severity of signs and symptoms. They are known as the mild form, the moderate form, the moderate/severe form, and the severe form. It is estimated that 20 to 30 percent of people with hereditary spherocytosis have the mild form, 60 to 70 percent have the moderate form, 10 percent have the moderate/severe form, and 3 to 5 percent have the severe form.People with the mild form may have very mild anemia or sometimes have no symptoms. People with the moderate form typically have anemia, jaundice, and splenomegaly. Many also develop gallstones. The signs and symptoms of moderate hereditary spherocytosis usually appear in childhood. Individuals with the moderate/severe form have all the features of the moderate form but also have severe anemia. Those with the severe form have life-threatening anemia that requires frequent blood transfusions to replenish their red blood cell supply. They also have severe splenomegaly, jaundice, and a high risk for developing gallstones. Some individuals with the severe form have short stature, delayed sexual development, and skeletal abnormalities.
Last Evaluated: Dec 15, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 17:44261625
OMIM Allelic Variant: 109270.0004
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Dec 15, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 17:44261625
OMIM Allelic Variant: 109270.0004
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Dec 15, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 17:44261625
OMIM Allelic Variant: 109270.0004
Moderate clinical importance, Uncertain pathogenic — Rare and reported to cause hemolytic anemia in a recessive manner, although insufficient data is published to establish statistical significance. Polyphen 2 predicts a benign effect.
Clinically Significant Conflicting/Uncertain
Hetero
Gene:
FAH
Variant:
c.1021C>T
(p.Arg341Trp)
rsID: rs11555096
Ref Allele: C
Alt Allele: T
Freq: 1.3371%uncommon
CADD: 24.5
ClinVar Submissions (4)
Last Evaluated: Jul 30, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: other
Assembly: GRCh38
Chromosome/Position: 15:80180184
OMIM Allelic Variant: 613871.0006
Untreated tyrosinemia type I usually presents either in young infants with severe liver involvement or later in the first year with liver dysfunction and renal tubular dysfunction associated with growth failure and rickets. Untreated children may have repeated, often unrecognized, neurologic crises lasting one to seven days that can include change in mental status, abdominal pain, peripheral neuropathy, and/or respiratory failure requiring mechanical ventilation. Death in the untreated child usually occurs before age ten years, typically from liver failure, neurologic crisis, or hepatocellular carcinoma. Combined treatment with nitisinone and a low-tyrosine diet has resulted in a greater than 90% survival rate, normal growth, improved liver function, prevention of cirrhosis, correction of renal tubular acidosis, and improvement in secondary rickets.
Last Evaluated: Jul 30, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: other
Assembly: GRCh38
Chromosome/Position: 15:80180184
OMIM Allelic Variant: 613871.0006
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jul 30, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: other
Assembly: GRCh38
Chromosome/Position: 15:80180184
OMIM Allelic Variant: 613871.0006
Low clinical importance, Uncertain benign — This variant shows pseudodeficiency for production of FAH protein which is connected with hereditary tyrosinemia type I. Pseudodeficiency was confirmed with site-directed mutagenesis and expression in a rabbit reticulocyte lysate system. The allelic frequency in 516 Norwegian controls was 0.022.
Clinically Significant
Hetero
Gene:
SRD5A2
Variant:
c.145G>A
(p.Ala49Thr)
rsID: rs9282858
Ref Allele: C
Alt Allele: T
Freq: 2.1391%uncommon
CADD: 19.39
ClinVar Submissions (4)
Last Evaluated: May 15, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:31580756
OMIM Allelic Variant: 607306.0012
Last Evaluated: May 15, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:31580756
OMIM Allelic Variant: 607306.0012
Last Evaluated: May 15, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:31580756
OMIM Allelic Variant: 607306.0012
Clinically Significant Benign
Hetero
Gene:
KRT85
Variant:
c.233G>A
(p.Arg78His)
rsID: rs61630004
Ref Allele: C
Alt Allele: T
Freq: 3.6012%uncommon
CADD: 17.51
ClinVar Submissions (3)
Some ectodermal dysplasias are here classified as congenital disorders characterized by abnormal development in 2 or more ectodermal structures (hair, nails, teeth, and sweat glands) without other systemic findings. Ectodermal dysplasia of the hair/nail type is a rare congenital condition characterized by hypotrichosis and nail dystrophy without nonectodermal or other ectodermal manifestations.
Last Evaluated: Mar 28, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 12:52367173
OMIM Allelic Variant: 602767.0001
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Mar 28, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 12:52367173
OMIM Allelic Variant: 602767.0001
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 28, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 12:52367173
OMIM Allelic Variant: 602767.0001
Low clinical importance, Uncertain benign — Presumed benign. Although this variant was implicated in causing ectodermal dysplasia in a recessive manner in two Pakistani families (one of which was large and consanguineous), GET-Evidence reports that the variant has been seen in 5 out of 114 random control chromosomes. This strongly contradicts a severe pathogenic effect.
Clinically Significant Benign
Hetero
Gene:
NTRK1
Variant:
c.1810C>T
(p.His604Tyr)
rsID: rs6336
Ref Allele: C
Alt Allele: T
Freq: 3.6411%uncommon
CADD: 26.2
ClinVar Submissions (6)
Multiple endocrine neoplasia type 2 (MEN 2) is classified into three subtypes: MEN 2A, FMTC (familial medullary thyroid carcinoma), and MEN 2B. All three subtypes involve high risk for development of medullary carcinoma of the thyroid (MTC); MEN 2A and MEN 2B have an increased risk for pheochromocytoma; MEN 2A has an increased risk for parathyroid adenoma or hyperplasia. Additional features in MEN 2B include mucosal neuromas of the lips and tongue, distinctive facies with enlarged lips, ganglioneuromatosis of the gastrointestinal tract, and a "marfanoid" habitus. MTC typically occurs in early childhood in MEN 2B, early adulthood in MEN 2A, and middle age in FMTC.
Last Evaluated: Oct 05, 2017
Review Status: no interpretation for the single variant
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 1:156879126
OMIM Allelic Variant: 191315.0005
Congenital insensitivity to pain with anhidrosis (CIPA), also known as hereditary sensory and autonomic neuropathy type IV (HSAN IV), is characterized by insensitivity to pain, anhidrosis (the inability to sweat), and intellectual disability. The ability to sense all pain (including visceral pain) is absent, resulting in repeated injuries including: oral self-mutilation (biting of tongue, lips, and buccal mucosa); biting of fingertips; bruising, scarring, and infection of the skin; multiple bone fractures (many of which fail to heal properly); and recurrent joint dislocations resulting in joint deformity. Sense of touch, vibration, and position are normal. Anhidrosis predisposes to recurrent febrile episodes that are often the initial manifestation of CIPA. Hypothermia in cold environments also occurs. Intellectual disability of varying degree is observed in most affected individuals; hyperactivity and emotional lability are common.
Last Evaluated: Oct 05, 2017
Review Status: no interpretation for the single variant
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 1:156879126
OMIM Allelic Variant: 191315.0005
Congenital insensitivity to pain with anhidrosis (CIPA), also known as hereditary sensory and autonomic neuropathy type IV (HSAN IV), is characterized by insensitivity to pain, anhidrosis (the inability to sweat), and intellectual disability. The ability to sense all pain (including visceral pain) is absent, resulting in repeated injuries including: oral self-mutilation (biting of tongue, lips, and buccal mucosa); biting of fingertips; bruising, scarring, and infection of the skin; multiple bone fractures (many of which fail to heal properly); and recurrent joint dislocations resulting in joint deformity. Sense of touch, vibration, and position are normal. Anhidrosis predisposes to recurrent febrile episodes that are often the initial manifestation of CIPA. Hypothermia in cold environments also occurs. Intellectual disability of varying degree is observed in most affected individuals; hyperactivity and emotional lability are common.
Last Evaluated: Oct 05, 2017
Review Status: no interpretation for the single variant
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 1:156879126
OMIM Allelic Variant: 191315.0005
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Oct 05, 2017
Review Status: no interpretation for the single variant
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 1:156879126
OMIM Allelic Variant: 191315.0005
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Oct 05, 2017
Review Status: no interpretation for the single variant
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 1:156879126
OMIM Allelic Variant: 191315.0005
Low clinical importance, Uncertain benign — Various databases and papers treat this variant as a non-pathogenic polymorphism, although it is fairly uncommon and is computational methods predict it to be damaging.
Clinically Significant Conflicting/Uncertain
Hetero
Gene:
NTRK1
Variant:
c.1730G>T
(p.Gly577Val)
rsID: rs6339
Ref Allele: G
Alt Allele: T
Freq: 3.645%uncommon
CADD: 22.1
ClinVar Submissions (7)
Multiple endocrine neoplasia type 2 (MEN 2) is classified into three subtypes: MEN 2A, FMTC (familial medullary thyroid carcinoma), and MEN 2B. All three subtypes involve high risk for development of medullary carcinoma of the thyroid (MTC); MEN 2A and MEN 2B have an increased risk for pheochromocytoma; MEN 2A has an increased risk for parathyroid adenoma or hyperplasia. Additional features in MEN 2B include mucosal neuromas of the lips and tongue, distinctive facies with enlarged lips, ganglioneuromatosis of the gastrointestinal tract, and a "marfanoid" habitus. MTC typically occurs in early childhood in MEN 2B, early adulthood in MEN 2A, and middle age in FMTC.
Last Evaluated: Oct 05, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 1:156879154
OMIM Allelic Variant: 191315.0005
Congenital insensitivity to pain with anhidrosis (CIPA), also known as hereditary sensory and autonomic neuropathy type IV (HSAN IV), is characterized by insensitivity to pain, anhidrosis (the inability to sweat), and intellectual disability. The ability to sense all pain (including visceral pain) is absent, resulting in repeated injuries including: oral self-mutilation (biting of tongue, lips, and buccal mucosa); biting of fingertips; bruising, scarring, and infection of the skin; multiple bone fractures (many of which fail to heal properly); and recurrent joint dislocations resulting in joint deformity. Sense of touch, vibration, and position are normal. Anhidrosis predisposes to recurrent febrile episodes that are often the initial manifestation of CIPA. Hypothermia in cold environments also occurs. Intellectual disability of varying degree is observed in most affected individuals; hyperactivity and emotional lability are common.
Last Evaluated: Oct 05, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 1:156879154
OMIM Allelic Variant: 191315.0005
Congenital insensitivity to pain with anhidrosis (CIPA), also known as hereditary sensory and autonomic neuropathy type IV (HSAN IV), is characterized by insensitivity to pain, anhidrosis (the inability to sweat), and intellectual disability. The ability to sense all pain (including visceral pain) is absent, resulting in repeated injuries including: oral self-mutilation (biting of tongue, lips, and buccal mucosa); biting of fingertips; bruising, scarring, and infection of the skin; multiple bone fractures (many of which fail to heal properly); and recurrent joint dislocations resulting in joint deformity. Sense of touch, vibration, and position are normal. Anhidrosis predisposes to recurrent febrile episodes that are often the initial manifestation of CIPA. Hypothermia in cold environments also occurs. Intellectual disability of varying degree is observed in most affected individuals; hyperactivity and emotional lability are common.
Last Evaluated: Oct 05, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 1:156879154
OMIM Allelic Variant: 191315.0005
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Oct 05, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 1:156879154
OMIM Allelic Variant: 191315.0005
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Oct 05, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 1:156879154
OMIM Allelic Variant: 191315.0005
Low clinical importance, Uncertain benign — Also called G607V, this variant has been reported as a nonpathogenic polymorphism.
Clinically Significant Conflicting/Uncertain
Hetero
Gene:
GAA
Variant:
c.2065G>A
(p.Glu689Lys)
rsID: rs1800309
Ref Allele: G
Alt Allele: A
Freq: 4.5426%uncommon
CADD: 18.3
ClinVar Submissions (8)
Last Evaluated: Jul 09, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 8
Clinical Significance: Conflicting interpretations of pathogenicity, other
Assembly: GRCh38
Chromosome/Position: 17:80113242
OMIM Allelic Variant: 606800.0011
Last Evaluated: Jul 09, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 8
Clinical Significance: Conflicting interpretations of pathogenicity, other
Assembly: GRCh38
Chromosome/Position: 17:80113242
OMIM Allelic Variant: 606800.0011
Last Evaluated: Jul 09, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 8
Clinical Significance: Conflicting interpretations of pathogenicity, other
Assembly: GRCh38
Chromosome/Position: 17:80113242
OMIM Allelic Variant: 606800.0011
Last Evaluated: Jul 09, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 8
Clinical Significance: Conflicting interpretations of pathogenicity, other
Assembly: GRCh38
Chromosome/Position: 17:80113242
OMIM Allelic Variant: 606800.0011
Low clinical importance, Uncertain benign — This is also known as the GAA*4 allozyme is frequent in the Asian population and appears to have somewhat reduced enzyme activity. Kroos et al. rule out pathogenic effect.
Clinically Significant Conflicting/Uncertain
Hetero
Gene:
MC1R
Variant:
c.478C>T
(p.Arg160Trp)
rsID: rs1805008
Ref Allele: C
Alt Allele: T
Freq: 4.6318%uncommon
CADD: 22.9
ClinVar Submissions (4)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity, Affects, association, risk factor
Assembly: GRCh38
Chromosome/Position: 16:89919736
OMIM Allelic Variant: 155555.0005
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity, Affects, association, risk factor
Assembly: GRCh38
Chromosome/Position: 16:89919736
OMIM Allelic Variant: 155555.0005
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity, Affects, association, risk factor
Assembly: GRCh38
Chromosome/Position: 16:89919736
OMIM Allelic Variant: 155555.0005
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity, Affects, association, risk factor
Assembly: GRCh38
Chromosome/Position: 16:89919736
OMIM Allelic Variant: 155555.0005
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity, Affects, association, risk factor
Assembly: GRCh38
Chromosome/Position: 16:89919736
OMIM Allelic Variant: 155555.0005
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity, Affects, association, risk factor
Assembly: GRCh38
Chromosome/Position: 16:89919736
OMIM Allelic Variant: 155555.0005
Clinically Significant Conflicting/Uncertain
Hetero
Gene:
RPGRIP1L
Variant:
c.685G>A
(p.Ala229Thr)
rsID: rs61747071
Ref Allele: C
Alt Allele: T
Freq: 5.0467%
CADD: 10.35
ClinVar Submissions (8)
Last Evaluated: Aug 08, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 8
Clinical Significance: Conflicting interpretations of pathogenicity, risk factor
Assembly: GRCh38
Chromosome/Position: 16:53686524
OMIM Allelic Variant: 610937.0013
Last Evaluated: Aug 08, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 8
Clinical Significance: Conflicting interpretations of pathogenicity, risk factor
Assembly: GRCh38
Chromosome/Position: 16:53686524
OMIM Allelic Variant: 610937.0013
Last Evaluated: Aug 08, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 8
Clinical Significance: Conflicting interpretations of pathogenicity, risk factor
Assembly: GRCh38
Chromosome/Position: 16:53686524
OMIM Allelic Variant: 610937.0013
Last Evaluated: Aug 08, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 8
Clinical Significance: Conflicting interpretations of pathogenicity, risk factor
Assembly: GRCh38
Chromosome/Position: 16:53686524
OMIM Allelic Variant: 610937.0013
Last Evaluated: Aug 08, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 8
Clinical Significance: Conflicting interpretations of pathogenicity, risk factor
Assembly: GRCh38
Chromosome/Position: 16:53686524
OMIM Allelic Variant: 610937.0013
Last Evaluated: Aug 08, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 8
Clinical Significance: Conflicting interpretations of pathogenicity, risk factor
Assembly: GRCh38
Chromosome/Position: 16:53686524
OMIM Allelic Variant: 610937.0013
Last Evaluated: Aug 08, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 8
Clinical Significance: Conflicting interpretations of pathogenicity, risk factor
Assembly: GRCh38
Chromosome/Position: 16:53686524
OMIM Allelic Variant: 610937.0013
Low clinical importance, Likely pathogenic — This variant is generally not considered pathogenic, but when combined with other severe variants it is associated with rare genetic diseases which involve retinal degeneration. Carrying this variant increases the risk of these diseases, but the overall increased risk is very small because the diseases are very rare.
Clinically Significant Conflicting/Uncertain
Hetero
Gene:
CLEC7A
Variant:
c.714T>G
(p.Tyr238Ter)
rsID: rs16910526
Ref Allele: A
Alt Allele: C
Freq: 5.5181%
CADD: 40
ClinVar Submissions (2)
Aspergillus species are ubiquitous in nature and cause a wide spectrum of diseases, including saprophytic colonization of existing cavities (aspergilloma), allergic asthma, hypersensitivity pneumonitis, allergic bronchopulmonary aspergillosis, and disseminated disease associated with high mortality rates in patients with hematologic malignancies and recipients of solid organs and stem cell transplantations. Immunocompetent and nonatopic individuals are relatively resistant to infection, and disease occurs in the setting of host damage. Association of persistent inflammation with intractable infection is common in nonneutropenic patients after hematopoietic stem cell transplantation, as well as in allergic fungal diseases. The pathophysiology underlying Aspergillus infection highlights the bipolar nature of the inflammatory process in infection, in which early inflammation prevents or limits infection, but an uncontrolled response may oppose disease eradication (summary by Cunha et al., 2010). For information on familial occurrence of allergic bronchopulmonary aspergillosis, see 103920.
Last Evaluated: Mar 29, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 12:10118488
OMIM Allelic Variant: 606264.0001
Familial candidiasis is an inherited tendency to develop infections caused by a type of fungus called Candida. Affected individuals typically have infections of the skin, the nails, and the moist lining of body cavities (mucous membranes). These infections are recurrent and persistent, which means they come back repeatedly and can last a long time. This pattern of infection is called chronic mucocutaneous candidiasis.Candida is commonly present on the skin and on the mucous membranes, and in most people usually causes no health problems. However, certain medications (such as antibiotics and corticosteroids) and other factors can lead to occasional overgrowth of Candida (candidiasis) in the mouth (where it is known as thrush) or in the vagina. These episodes, commonly called yeast infections, usually last only a short time before being cleared by a healthy immune system.Most people with familial candidiasis have chronic or recurrent yeast infections that begin in early childhood. Skin infections lead to a rash with crusty, thickened patches; when these patches occur on the scalp, they can cause loss of hair in the affected area (scarring alopecia). Candidiasis of the nails can result in thick, cracked, and discolored nails and swelling and redness of the surrounding skin. Thrush and gastrointestinal symptoms such as bloating, constipation, or diarrhea are common in affected individuals. Women with familial candidiasis can develop frequent vaginal yeast infections, and infants can have yeast infections on the skin that cause persistent diaper rash.Depending on the genetic change involved in this condition, some affected individuals are at risk for developing systemic candidiasis, a more severe condition in which the infection spreads through the bloodstream to various organs including the brain and the meninges, which are the membranes covering the brain and spinal cord. Systemic candidiasis can be life-threatening.Chronic or recurrent yeast infections can occur in people without familial candidiasis. Some individuals experience recurrent candidiasis as part of a general susceptibility to infections because their immune systems are impaired by a disease such as acquired immune deficiency syndrome (AIDS) or severe combined immunodeficiency (SCID), medications, or other factors. Other individuals have syndromes such as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) or autosomal dominant hyper-IgE syndrome (AD-HIES) that include a tendency to develop candidiasis along with other signs and symptoms affecting various organs and systems of the body.
Last Evaluated: Mar 29, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 12:10118488
OMIM Allelic Variant: 606264.0001
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 29, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 12:10118488
OMIM Allelic Variant: 606264.0001
Low clinical importance, Uncertain pathogenic — This variant has been found to impair homan mucosal antifungal defense and was implicated in vulvovaginal candidiasis and mucocutaneous infections in a Dutch family.
Clinically Significant Benign
Hetero
Gene:
CSRP3
Variant:
c.336G>A
(p.Ala112=)
rsID: rs13451
Ref Allele: C
Alt Allele: T
Freq: 6.692%
CADD: 3.721
ClinVar Submissions (7)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 11:19186294
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 11:19186294
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 11:19186294
A condition in which the myocardium is hypertrophied without an obvious cause. The hypertrophy is generally asymmetric and may be associated with obstruction of the ventricular outflow tract.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 11:19186294
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 11:19186294
Clinically Significant Conflicting/Uncertain
Hetero
Gene:
GHRL
Variant:
c.178C>A
(p.Leu60Met)
rsID: rs696217
Ref Allele: G
Alt Allele: T
Freq: 6.8481%
CADD: 22.8
ClinVar Submissions (1)
Last Evaluated: Dec 01, 2005
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Pathogenic, risk factor
Assembly: GRCh38
Chromosome/Position: 3:10289773
OMIM Allelic Variant: 605353.0002
Last Evaluated: Dec 01, 2005
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Pathogenic, risk factor
Assembly: GRCh38
Chromosome/Position: 3:10289773
OMIM Allelic Variant: 605353.0002
Clinically Significant Pathogenic, risk factor
Hetero
Gene:
FECH
Variant:
c.315-48T>C
rsID: rs2272783
Ref Allele: A
Alt Allele: G
Freq: 7.2288%
CADD: 5.052
ClinVar Submissions (4)
Red discoloration of the skin caused by infectious agents, inflammation, drug hypersensitivity, or underlying disease.
Last Evaluated: Aug 22, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 4
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 18:57571588
OMIM Allelic Variant: 612386.0015
Erythropoietic protoporphyria (EPP) is characterized by cutaneous photosensitivity (usually beginning in infancy or childhood) that results in tingling, burning, pain, and itching within 30 minutes after exposure to sun or ultraviolet light and may be accompanied by swelling and redness. Symptoms (which may seem out of proportion to the visible skin lesions) may persist for hours or days after the initial phototoxic reaction. Photosensitivity remains for life. Multiple episodes of acute photosensitivity may lead to chronic changes of sun-exposed skin (lichenification, leathery pseudovesicles, grooving around the lips) and loss of lunulae of the nails. Approximately 20%-30% of individuals with EPP have some degree of liver dysfunction, which is typically mild with slight elevations of the liver enzymes. Up to 5% may develop more advanced liver disease which may be accompanied by motor neuropathy similar to that seen in the acute porphyrias.
Last Evaluated: Aug 22, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 4
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 18:57571588
OMIM Allelic Variant: 612386.0015
A clinical manifestation of HYPERBILIRUBINEMIA, characterized by the yellowish staining of the SKIN; MUCOUS MEMBRANE; and SCLERA. Clinical jaundice usually is a sign of LIVER dysfunction.
Last Evaluated: Aug 22, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 4
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 18:57571588
OMIM Allelic Variant: 612386.0015
Clinically Significant Pathogenic
Hetero
Gene:
AMPD1
Variant:
c.133C>T
(p.Gln45Ter)
rsID: rs17602729
Ref Allele: G
Alt Allele: A
Freq: 8.0697%
CADD: 36
ClinVar Submissions (6)
Myoadenylate deaminase deficiency (MMDD) is an autosomal recessive condition that can manifest as exercise-induced muscle pain, occasionally associated with rhabdomyolysis and/or increased serum creatine kinase, or even infantile hypotonia. However, the finding of homozygous mutations among asymptomatic individuals have suggested to some (e.g., Verzijl et al., 1998) that AMPD1 deficiency may be a harmless entity (summary by Castro-Gago et al., 2011). Genetta et al. (2001) stated that AMPD1 deficiency is the most prevalent genetic disease in humans, the number of people heterozygous approaching 10% of Caucasians and individuals of African descent (Sabina et al., 1989). A small percentage of homozygous-deficient individuals, approximately 1.8% of the population, display symptoms of chronic fatigue and lost productivity as well as a predisposition to stress-related ailments, including heart disease and stroke, according to Genetta et al. (2001).
Last Evaluated: Jun 27, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity, other
Assembly: GRCh38
Chromosome/Position: 1:114693436
OMIM Allelic Variant: 102770.0001
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jun 27, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity, other
Assembly: GRCh38
Chromosome/Position: 1:114693436
OMIM Allelic Variant: 102770.0001
Low clinical importance, Likely pathogenic — Causes Adenosine Deaminase Deficiency in a recessive manner. Most of the time individuals do not report symptoms, but when symptoms do exist they to be post-exercise symptoms of muscle weakness, muscle pain, and getting tired more quickly.
Expert Reviewed Clinically Significant Conflicting/Uncertain
Hetero
Gene:
GNPAT
Variant:
c.1556A>G
(p.Asp519Gly)
rsID: rs11558492
Ref Allele: A
Alt Allele: G
Freq: 16.5934%
CADD: 22.1
ClinVar Submissions (6)
An autosomal recessive form of CHONDRODYSPLASIA PUNCTATA characterized by defective plasmalogen biosynthesis and impaired peroxisomes. Patients have shortened proximal limbs and severely disturbed endochondral bone formation. The metabolic defects associated with the impaired peroxisomes are present only in the rhizomelic form of chondrodysplasia punctata. (From Scriver et al, Metabolic Basis of Inherited Disease, 6th ed, p1497)
Last Evaluated: Sep 27, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 1:231272345
OMIM Allelic Variant: 602744.0006
Rhizomelic chondrodysplasia punctata (RCDP) is a peroxisomal disorder characterized by disproportionately short stature primarily affecting the proximal parts of the extremities, a typical facial appearance including a broad nasal bridge, epicanthus, high-arched palate, dysplastic external ears, and micrognathia, congenital contractures, characteristic ocular involvement, dwarfism, and severe mental retardation with spasticity. Biochemically, plasmalogen synthesis and phytanic acid alpha-oxidation are defective. Most patients die in the first decade of life. RCDP1 (215100) is the most frequent form of RCDP (summary by Wanders and Waterham, 2005). Whereas RCDP1 is a peroxisomal biogenesis disorder (PBD), RCDP2 is classified as a single peroxisome enzyme deficiency (Waterham and Ebberink, 2012). For a discussion of genetic heterogeneity of rhizomelic chondrodysplasia punctata, see 215100.
Last Evaluated: Sep 27, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 1:231272345
OMIM Allelic Variant: 602744.0006
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Sep 27, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 1:231272345
OMIM Allelic Variant: 602744.0006
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Sep 27, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 1:231272345
OMIM Allelic Variant: 602744.0006
Clinically Significant Conflicting/Uncertain
Homo
Gene:
DCAF17
Variant:
c.322-14C>T
rsID: rs192861143
Ref Allele: C
Alt Allele: T
Freq: 19.6125%
CADD: 1.57
ClinVar Submissions (3)
Neurodegeneration with brain iron accumulation (NBIA) is a group of inherited neurologic disorders in which iron accumulates in the basal ganglia resulting in progressive dystonia, spasticity, parkinsonism, neuropsychiatric abnormalities, and optic atrophy or retinal degeneration. Ten types and their associated genes are recognized. The age of onset ranges from infancy to late adulthood; the rate of progression varies. Cognitive decline occurs in some subtypes, but more often cognition is relatively spared. Cerebellar atrophy is a frequent finding in some subtypes.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:171448667
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:171448667
Clinically Significant Benign
Hetero
Gene:
ACADS
Variant:
c.625G>A
(p.Gly209Ser)
rsID: rs1799958
Ref Allele: G
Alt Allele: A
Freq: 19.974%
CADD: 28.1
ClinVar Submissions (8)
Most infants with short-chain acyl-CoA dehydrogenase deficiency (SCADD) identified through newborn screening programs have remained well, and asymptomatic relatives who meet diagnostic criteria are reported. Thus, SCADD is now viewed as a biochemical phenotype rather than a disease. A broad range of clinical findings was originally reported in those with confirmed SCADD, including severe dysmorphic facial features, feeding difficulties / failure to thrive, metabolic acidosis, ketotic hypoglycemia, lethargy, developmental delay, seizures, hypotonia, dystonia, and myopathy. However, individuals with no symptoms were also reported. In a large series of affected individuals detected on metabolic evaluation for developmental delay, 20% had failure to thrive, feeding difficulties, and hypotonia; 22% had seizures; and 30% had hypotonia without seizures. In contrast, the majority of infants with SCADD have been detected by expanded newborn screening, and the great majority of these infants remain asymptomatic. As with other fatty acid oxidation deficiencies, characteristic biochemical findings of SCADD may be absent except during times of physiologic stress such as fasting and illness. A diagnosis of SCADD based on clinical findings should not preclude additional testing to look for other causes.
Last Evaluated: Jul 04, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 8
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 12:120738280
OMIM Allelic Variant: 606885.0007
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jul 04, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 8
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 12:120738280
OMIM Allelic Variant: 606885.0007
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 04, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 8
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 12:120738280
OMIM Allelic Variant: 606885.0007
Clinically Significant Conflicting/Uncertain
Hetero
Gene:
RPGRIP1
Variant:
c.1639G>T
(p.Ala547Ser)
rsID: rs10151259
Ref Allele: G
Alt Allele: T
Freq: 20.3834%
CADD: 23.1
ClinVar Submissions (7)
Last Evaluated: Oct 21, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 14:21321881
OMIM Allelic Variant: 605446.0006
Cone-rod dystrophy is a group of related eye disorders that causes vision loss, which becomes more severe over time. These disorders affect the retina, which is the layer of light-sensitive tissue at the back of the eye. In people with cone-rod dystrophy, vision loss occurs as the light-sensing cells of the retina gradually deteriorate.The first signs and symptoms of cone-rod dystrophy, which often occur in childhood, are usually decreased sharpness of vision (visual acuity) and increased sensitivity to light (photophobia). These features are typically followed by impaired color vision (dyschromatopsia), blind spots (scotomas) in the center of the visual field, and partial side (peripheral) vision loss. Over time, affected individuals develop night blindness and a worsening of their peripheral vision, which can limit independent mobility. Decreasing visual acuity makes reading increasingly difficult and most affected individuals are legally blind by mid-adulthood. As the condition progresses, individuals may develop involuntary eye movements (nystagmus).There are more than 30 types of cone-rod dystrophy, which are distinguished by their genetic cause and their pattern of inheritance: autosomal recessive, autosomal dominant, and X-linked. Additionally, cone-rod dystrophy can occur alone without any other signs and symptoms or it can occur as part of a syndrome that affects multiple parts of the body.
Last Evaluated: Oct 21, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 14:21321881
OMIM Allelic Variant: 605446.0006
Leber congenital amaurosis comprises a group of early-onset childhood retinal dystrophies characterized by vision loss, nystagmus, and severe retinal dysfunction. Patients usually present at birth with profound vision loss and pendular nystagmus. Electroretinogram (ERG) responses are usually nonrecordable. Other clinical findings may include high hypermetropia, photodysphoria, oculodigital sign, keratoconus, cataracts, and a variable appearance to the fundus (summary by Chung and Traboulsi, 2009). Genetic Heterogeneity of Leber Congenital Amaurosis LCA2 (204100) is caused by mutation in the RPE65 gene (RPE65; 180069) on chromosome 1p31. LCA3 (604232) is caused by mutation in the SPATA7 gene (609868) on chromosome 14q31. LCA4 (604393) is caused by mutation in the AIPL1 gene (604392) on chromosome 17p13. LCA5 (604537) is caused by mutation in the LCA5 gene (611408) on chromosome 6q14. LCA6 (613826) is caused by mutation in the RPGRIP1 gene (605446) on chromosome 14q11. LCA7 (613829) is caused by mutation in the CRX gene (602225) on chromosome 19q13. LCA8 (613835) is caused by mutation in the CRB1 gene (604210) on chromosome 1q31. LCA9 (608553) is caused by mutation in the NMNAT1 gene (608700) on chromosome 1p36. LCA10 (611755) is caused by mutation in the CEP290 gene (610142) on chromosome 12q21 and may account for as many as 21% of cases of LCA. LCA11 (613837) is caused by mutation in the IMPDH1 gene (146690) on chromosome 7q32. LCA12 (610612) is caused by mutation in the RD3 gene (180040) on chromosome 1q32. LCA13 (612712) is caused by mutation in the RDH12 gene (608830) on chromosome 14q24. LCA14 (613341) is caused by mutation in the LRAT gene (604863) on chromosome 4q32. LCA15 (613843) is caused by mutation in the TULP1 gene (602280) on chromosome 6p21. LCA16 (614186) is caused by mutation in the KCNJ13 gene (603208) on chromosome 2q37. LCA17 (615360) is caused by mutation in the GDF6 gene (601147) on chromosome 8q22. LCA18 (see 608133) is caused by mutation in the PRPH2 gene (179605) on chromosome 6p21. Perrault et al. (1999) provided a review of Leber congenital amaurosis, with emphasis on genetic heterogeneity. Wiszniewski et al. (2011) analyzed 13 known LCA genes in 60 LCA probands, and identified homozygous or compound heterozygous mutations in 42 (70%). In addition, a third disease-associated mutant allele at a second locus was identified in 7 (12%) of the 60 patients. Wiszniewski et al. (2011) stated that the significance of the third mutated allele was unknown, but suggested that mutational load might be important to penetrance of the LCA phenotype. Because LCA manifests very early in life and results in profound vision loss, patients with mutations in other syndromic or nonsyndromic eye disease genes may receive an initial diagnosis of LCA, prior to development of syndromic features or before more thorough phenotyping can be performed (see, e.g., Senior-Loken syndrome-5, 609254).
Last Evaluated: Oct 21, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 14:21321881
OMIM Allelic Variant: 605446.0006
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Oct 21, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 14:21321881
OMIM Allelic Variant: 605446.0006
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Oct 21, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 14:21321881
OMIM Allelic Variant: 605446.0006
Low clinical importance, Uncertain benign — Probably benign. Implicated in causing autosomal recessive cone-rod dystrophy, but a later report found the same incidence in controls and concludes it is not causal.
Clinically Significant Conflicting/Uncertain
Hetero
Gene:
ABCC6
Variant:
c.3803G>A
(p.Arg1268Gln)
rsID: rs2238472
Ref Allele: C
Alt Allele: T
Freq: 21.4362%
CADD: 16.44
ClinVar Submissions (3)
Pseudoxanthoma elasticum (PXE) is a systemic disorder that affects the elastic tissue of the skin, the eye, and the cardiovascular and gastrointestinal systems. Individuals most commonly present with papules in the skin and/or with angioid streaks of the retina found on routine eye examination or associated with retinal hemorrhage. Rarely, individuals may present with vascular signs and symptoms, such as gastrointestinal bleeding, angina, or intermittent claudication. The most frequent cause of morbidity and disability in PXE is reduced vision from macular hemorrhage and disciform scarring of the macula. Most affected individuals live a normal life span.
Last Evaluated: May 23, 2000
Review Status: criteria provided, single submitter
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 16:16157742
OMIM Allelic Variant: 603234.0011
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: May 23, 2000
Review Status: criteria provided, single submitter
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 16:16157742
OMIM Allelic Variant: 603234.0011
Low clinical importance, Uncertain pharmacogenetic — This common polymorphism appears to not have a significant phenotypic impact. A few studies report weak but significant associations with plasma lipids (in Inuits) and thalidomide toxicity.
Clinically Significant Benign
Hetero
Gene:
NPHS2
Variant:
c.-51G>T
rsID: rs12406197
Ref Allele: C
Alt Allele: A
Freq: 22.9071%
CADD: 3.928
ClinVar Submissions (2)
Steroid-resistant nephrotic syndrome type 2 is an autosomal recessive disorder characterized clinically by childhood onset of proteinuria, hypoalbuminemia, hyperlipidemia, and edema. Kidney biopsies show nonspecific histologic changes such as minimal change, focal segmental glomerulosclerosis (FSGS), and diffuse mesangial proliferation. The disorder is resistant to steroid treatment and progresses to end-stage renal failure in the first or second decades (summary by Fuchshuber et al., 1996). Some patients show later onset of the disorder (Tsukaguchi et al., 2002). For a general phenotypic description and a discussion of genetic heterogeneity of nephrotic syndrome and FSGS, see NPHS1 (256300).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:179575915
Steroid-resistant nephrotic syndrome type 2 is an autosomal recessive disorder characterized clinically by childhood onset of proteinuria, hypoalbuminemia, hyperlipidemia, and edema. Kidney biopsies show nonspecific histologic changes such as minimal change, focal segmental glomerulosclerosis (FSGS), and diffuse mesangial proliferation. The disorder is resistant to steroid treatment and progresses to end-stage renal failure in the first or second decades (summary by Fuchshuber et al., 1996). Some patients show later onset of the disorder (Tsukaguchi et al., 2002). For a general phenotypic description and a discussion of genetic heterogeneity of nephrotic syndrome and FSGS, see NPHS1 (256300).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:179575915
A form of nephrotic syndrome that does not respond to treatment with steroid medication.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:179575915
Clinically Significant Likely benign
Hetero
Gene:
DPYD
Variant:
c.85T>C
(p.Cys29Arg)
rsID: rs1801265
Ref Allele: A
Alt Allele: G
Freq: 26.5426%
CADD: 19.05
ClinVar Submissions (2)
Last Evaluated: Nov 20, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:97883329
OMIM Allelic Variant: 612779.0004
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Nov 20, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:97883329
OMIM Allelic Variant: 612779.0004
Insufficiently evaluated pharmacogenetic — This variant is also known as DPYD*9A, and is associated with Dihydropyrimidine dehydrogenase deficiency and impaired clearance of 5-fluorouracil with potential toxic consequence.
Clinically Significant Benign
Hetero
Gene:
FECH
Variant:
c.68-23C>T
rsID: rs2269219
Ref Allele: G
Alt Allele: A
Freq: 27.9697%
CADD: 1.754
ClinVar Submissions (2)
Red discoloration of the skin caused by infectious agents, inflammation, drug hypersensitivity, or underlying disease.
Last Evaluated: Jan 25, 2016
Review Status: no assertion criteria provided
Number of Submitters: 2
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 18:57580222
OMIM Allelic Variant: 612386.0003
Erythropoietic protoporphyria (EPP) is characterized by cutaneous photosensitivity (usually beginning in infancy or childhood) that results in tingling, burning, pain, and itching within 30 minutes after exposure to sun or ultraviolet light and may be accompanied by swelling and redness. Symptoms (which may seem out of proportion to the visible skin lesions) may persist for hours or days after the initial phototoxic reaction. Photosensitivity remains for life. Multiple episodes of acute photosensitivity may lead to chronic changes of sun-exposed skin (lichenification, leathery pseudovesicles, grooving around the lips) and loss of lunulae of the nails. Approximately 20%-30% of individuals with EPP have some degree of liver dysfunction, which is typically mild with slight elevations of the liver enzymes. Up to 5% may develop more advanced liver disease which may be accompanied by motor neuropathy similar to that seen in the acute porphyrias.
Last Evaluated: Jan 25, 2016
Review Status: no assertion criteria provided
Number of Submitters: 2
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 18:57580222
OMIM Allelic Variant: 612386.0003
A clinical manifestation of HYPERBILIRUBINEMIA, characterized by the yellowish staining of the SKIN; MUCOUS MEMBRANE; and SCLERA. Clinical jaundice usually is a sign of LIVER dysfunction.
Last Evaluated: Jan 25, 2016
Review Status: no assertion criteria provided
Number of Submitters: 2
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 18:57580222
OMIM Allelic Variant: 612386.0003
Clinically Significant Conflicting/Uncertain
Homo
Gene:
GCDH
Variant:
c.852+223C>T
rsID: rs11085825
Ref Allele: C
Alt Allele: T
Freq: 30.6846%
CADD: 1.467
ClinVar Submissions (1)
Glutaric acidemia I is an autosomal recessive metabolic disorder characterized by gliosis and neuronal loss in the basal ganglia and a progressive movement disorder that usually begins during the first year of life (Goodman et al., 1995). Hedlund et al. (2006) provided a detailed review of the clinical and biochemical aspects of glutaric acidemia type I.
Last Evaluated: Dec 08, 2015
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Likely pathogenic
Assembly: GRCh38
Chromosome/Position: 19:12896644
Clinically Significant Likely pathogenic
Hetero
Gene:
GCDH
Variant:
c.*288G>T
rsID: rs9384
Ref Allele: G
Alt Allele: T
Freq: 33.4719%
CADD: 1.464
ClinVar Submissions (2)
An increased concentration of glutaric acid in the blood.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 19:12899829
Glutaric acidemia I is an autosomal recessive metabolic disorder characterized by gliosis and neuronal loss in the basal ganglia and a progressive movement disorder that usually begins during the first year of life (Goodman et al., 1995). Hedlund et al. (2006) provided a detailed review of the clinical and biochemical aspects of glutaric acidemia type I.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 19:12899829
Clinically Significant Benign
Hetero
Gene:
GATA4
Variant:
c.*1256A>T
rsID: rs12458
Ref Allele: A
Alt Allele: T
Freq: 35.6221%
CADD: 2.229
ClinVar Submissions (1)
Critical congenital heart disease (CCHD) is a term that refers to a group of serious heart defects that are present from birth. These abnormalities result from problems with the formation of one or more parts of the heart during the early stages of embryonic development. CCHD prevents the heart from pumping blood effectively or reduces the amount of oxygen in the blood. As a result, organs and tissues throughout the body do not receive enough oxygen, which can lead to organ damage and life-threatening complications. Individuals with CCHD usually require surgery soon after birth.Although babies with CCHD may appear healthy for the first few hours or days of life, signs and symptoms soon become apparent. These can include an abnormal heart sound during a heartbeat (heart murmur), rapid breathing (tachypnea), low blood pressure (hypotension), low levels of oxygen in the blood (hypoxemia), and a blue or purple tint to the skin caused by a shortage of oxygen (cyanosis). If untreated, CCHD can lead to shock, coma, and death. However, most people with CCHD now survive past infancy due to improvements in early detection, diagnosis, and treatment.Some people with treated CCHD have few related health problems later in life. However, long-term effects of CCHD can include delayed development and reduced stamina during exercise. Adults with these heart defects have an increased risk of abnormal heart rhythms, heart failure, sudden cardiac arrest, stroke, and premature death.Each of the heart defects associated with CCHD affects the flow of blood into, out of, or through the heart. Some of the heart defects involve structures within the heart itself, such as the two lower chambers of the heart (the ventricles) or the valves that control blood flow through the heart. Others affect the structure of the large blood vessels leading into and out of the heart (including the aorta and pulmonary artery). Still others involve a combination of these structural abnormalities.People with CCHD have one or more specific heart defects. The heart defects classified as CCHD include coarctation of the aorta, double-outlet right ventricle, D-transposition of the great arteries, Ebstein anomaly, hypoplastic left heart syndrome, interrupted aortic arch, pulmonary atresia with intact septum, single ventricle, total anomalous pulmonary venous connection, tetralogy of Fallot, tricuspid atresia, and truncus arteriosus.
Last Evaluated: Jan 07, 2017
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 8:11759731
Clinically Significant Pathogenic
Hetero
Gene:
ACTN3
Variant:
c.1729C>T
(p.Arg577Ter)
rsID: rs1815739
Ref Allele: C
Alt Allele: T
Freq: 37.4841%
CADD: 40
ClinVar Submissions (1)
Last Evaluated: Oct 27, 2017
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Conflicting interpretations of pathogenicity, Affects
Assembly: GRCh38
Chromosome/Position: 11:66560624
OMIM Allelic Variant: 102574.0001
Last Evaluated: Oct 27, 2017
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Conflicting interpretations of pathogenicity, Affects
Assembly: GRCh38
Chromosome/Position: 11:66560624
OMIM Allelic Variant: 102574.0001
Last Evaluated: Oct 27, 2017
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Conflicting interpretations of pathogenicity, Affects
Assembly: GRCh38
Chromosome/Position: 11:66560624
OMIM Allelic Variant: 102574.0001
Clinically Significant Conflicting/Uncertain
Hetero
Gene:
PRSS1
Variant:
c.47C>T
(p.Ala16Val)
rsID: rs202003805
Ref Allele: C
Alt Allele: T
Freq: 40.938%
CADD: 0.048
ClinVar Submissions (6)
A disorder characterized by recurrent episodes of pancreatitis that start at a young age. It is caused by mutations in the PRSS1 or SPINK1 genes. Patients are at a high risk of developing pancreatic carcinoma.
Last Evaluated: Apr 15, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 7:142750561
A recurrent form of pancreatitis. [HPO:probinson]
Last Evaluated: Apr 15, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 7:142750561
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Apr 15, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 7:142750561
Clinically Significant Conflicting/Uncertain
Hetero
Gene:
CYP4V2
Variant:
c.64C>G
(p.Leu22Val)
rsID: rs1055138
Ref Allele: C
Alt Allele: G
Freq: 45.4383%
CADD: 3.733
ClinVar Submissions (6)
Bietti crystalline dystrophy (BCD) is a chorioretinal degeneration characterized by the presence of yellow-white crystals and/or complex lipid deposits in the retina and (to a variable degree) the cornea. Progressive atrophy and degeneration of the retinal pigment epithelium (RPE) / choroid lead to symptoms similar to those of other forms of retinal degeneration that fall under the category of retinitis pigmentosa and allied disorders, namely: reduced visual acuity, poor night vision, abnormal retinal electrophysiology, visual field loss, and often impaired color vision. Marked asymmetry between eyes is not uncommon. Onset is typically during the second to third decade of life, but ranges from the early teenage years to beyond the third decade. With time, loss of peripheral visual field, central acuity, or both result in legal blindness in most if not all affected individuals.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 4:186191887
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 4:186191887
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 4:186191887
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 4:186191887
Clinically Significant Benign
Homo
Gene:
COL4A4
Variant:
c.3979G>A
(p.Val1327Met)
rsID: rs2229813
Ref Allele: C
Alt Allele: T
Freq: 46.2371%
CADD: 2.045
ClinVar Submissions (6)
Alport syndrome is a genetic condition characterized by kidney disease, hearing loss, and eye abnormalities.People with Alport syndrome experience progressive loss of kidney function. Almost all affected individuals have blood in their urine (hematuria), which indicates abnormal functioning of the kidneys. Many people with Alport syndrome also develop high levels of protein in their urine (proteinuria). The kidneys become less able to function as this condition progresses, resulting in end-stage renal disease (ESRD).People with Alport syndrome frequently develop sensorineural hearing loss, which is caused by abnormalities of the inner ear, during late childhood or early adolescence. Affected individuals may also have misshapen lenses in the eyes (anterior lenticonus) and abnormal coloration of the light-sensitive tissue at the back of the eye (retina). These eye abnormalities seldom lead to vision loss.Significant hearing loss, eye abnormalities, and progressive kidney disease are more common in males with Alport syndrome than in affected females.
Last Evaluated: May 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:227028004
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: May 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:227028004
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: May 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:227028004
Clinically Significant Benign
Homo
Gene:
MIR181A1HG
Variant:
n.364-18748G>A
rsID: rs12406470
Ref Allele: C
Alt Allele: T
Freq: 46.3358%
CADD: 2.063
ClinVar Submissions (1)
An acute myeloid leukemia (AML) characterized by blasts with evidence of maturation to more mature neutrophils. (WHO, 2001)
Last Evaluated: -
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Pathogenic
Assembly: GRCh38
Chromosome/Position: 1:198826991
Clinically Significant Pathogenic
Hetero
Gene:
CCR5
Variant:
c.-301+246A>G
rsID: rs1799987
Ref Allele: A
Alt Allele: G
Freq: 49.3884%
CADD: 2.992
ClinVar Submissions (1)
Last Evaluated: Jul 08, 2003
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Conflicting interpretations of pathogenicity, protective
Assembly: GRCh38
Chromosome/Position: 3:46370444
OMIM Allelic Variant: 601373.0006
Last Evaluated: Jul 08, 2003
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Conflicting interpretations of pathogenicity, protective
Assembly: GRCh38
Chromosome/Position: 3:46370444
OMIM Allelic Variant: 601373.0006
Last Evaluated: Jul 08, 2003
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Conflicting interpretations of pathogenicity, protective
Assembly: GRCh38
Chromosome/Position: 3:46370444
OMIM Allelic Variant: 601373.0006
Clinically Significant Conflicting/Uncertain
Hetero
Below are rare variants (frequency less than 1%) that were submitted to ClinVar. The data presented has no guarantees of reporting accuracy. Heterozygous variants are reported as yellow and homozygous variants as red. A red or yellow variant does not necessarily mean one has or carries a condition or disease. This is for research and educational purposes only.
Gene:
SCN1A
Variant:
c.4793A>T
(p.Tyr1598Phe)
rsID: rs377325221
Ref Allele: T
Alt Allele: A
Freq: 0.0016%rare
CADD: 27.8
ClinVar Submissions (3)
Last Evaluated: Aug 24, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:165994205
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Aug 24, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:165994205
Clinically Significant Conflicting/Uncertain
Hetero
Gene:
TGFBR2
Variant:
c.1060G>A
(p.Ala354Thr)
rsID: rs148665451
Ref Allele: G
Alt Allele: A
Freq: 0.0064%rare
CADD: 15.19
ClinVar Submissions (2)
Loeys-Dietz syndrome (LDS) is characterized by vascular findings (cerebral, thoracic, and abdominal arterial aneurysms and/or dissections), skeletal manifestations (pectus excavatum or pectus carinatum, scoliosis, joint laxity, arachnodactyly, talipes equinovarus, cervical spine malformation and/or instability), craniofacial features (widely spaced eyes, strabismus, bifid uvula / cleft palate, and craniosynostosis that can involve any sutures), and cutaneous findings (velvety and translucent skin, easy bruising, and dystrophic scars). Individuals with LDS are predisposed to widespread and aggressive arterial aneurysms and pregnancy-related complications including uterine rupture and death. Individuals with LDS can show a strong predisposition for allergic/inflammatory disease including asthma, eczema, and reactions to food or environmental allergens. There is also an increased incidence of gastrointestinal inflammation including eosinophilic esophagitis and gastritis or inflammatory bowel disease. Wide variation in the distribution and severity of clinical features can be seen in individuals with LDS, even among affected individuals within a family who have the same pathogenic variant.
Last Evaluated: Aug 19, 2014
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 3:30672168
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 19, 2014
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 3:30672168
Conflicting/Uncertain
Hetero
Gene:
EGR2
Variant:
c.540C>T
(p.Asp180=)
rsID: rs200913249
Ref Allele: G
Alt Allele: A
Freq: 0.008%rare
CADD: 14.76
ClinVar Submissions (1)
Charcot-Marie-Tooth disease encompasses a group of disorders called hereditary sensory and motor neuropathies that damage the peripheral nerves. Peripheral nerves connect the brain and spinal cord to muscles and to sensory cells that detect sensations such as touch, pain, heat, and sound. Damage to the peripheral nerves that worsens over time can result in alteration or loss of sensation and wasting (atrophy) of muscles in the feet, legs, and hands.Charcot-Marie-Tooth disease usually becomes apparent in adolescence or early adulthood, but onset may occur anytime from early childhood through late adulthood. Symptoms of Charcot-Marie-Tooth disease vary in severity and age of onset even among members of the same family. Some people never realize they have the disorder because their symptoms are so mild, but most have a moderate amount of physical disability. A small percentage of people experience severe weakness or other problems which, in very rare cases, can be life-threatening. In most affected individuals, however, Charcot-Marie-Tooth disease does not affect life expectancy.Typically, the earliest symptoms of Charcot-Marie-Tooth disease result from muscle atrophy in the feet. Affected individuals may have foot abnormalities such as high arches (pes cavus), flat feet (pes planus), or curled toes (hammer toes). They often have difficulty flexing the foot or walking on the heel of the foot. These difficulties may cause a higher than normal step (steppage gait) and increase the risk of ankle injuries and tripping. As the disease worsens, muscles in the lower legs usually weaken, but leg and foot problems rarely require the use of a wheelchair.Affected individuals may also develop weakness in the hands, causing difficulty with daily activities such as writing, fastening buttons, and turning doorknobs. People with Charcot-Marie-Tooth disease typically experience a decreased sensitivity to touch, heat, and cold in the feet and lower legs, but occasionally feel aching or burning sensations. In rare cases, affected individuals have loss of vision or gradual hearing loss that sometimes leads to deafness.There are several types of Charcot-Marie-Tooth disease, which are differentiated by their effects on nerve cells and patterns of inheritance. Type 1 (CMT1) is characterized by abnormalities in myelin, the fatty substance that covers nerve cells, protecting them and helping to transmit nerve impulses. These abnormalities slow the transmission of nerve impulses and can affect the health of the nerve fiber. Type 2 (CMT2) is characterized by abnormalities in the fiber, or axon, that extends from a nerve cell body to muscles or to sense organs. These abnormalities reduce the strength of the nerve impulse. In forms of Charcot-Marie-Tooth disease classified as intermediate type, the nerve impulses are both slowed and reduced in strength, probably due to abnormalities in both myelin and axons. Type 4 (CMT4) is distinguished from the other types by its pattern of inheritance; it can affect either the axons or the myelin. Type X Charcot-Marie-Tooth disease (CMTX) is caused by mutations in genes on the X chromosome, one of the two sex chromosomes. Within the various types of Charcot-Marie-Tooth disease, subtypes (such as CMT1A, CMT1B, CMT2A, CMT4A, and CMTX1) indicate different genetic causes.Sometimes other, historical names are used to refer to particular forms of Charcot-Marie-Tooth disease. For example, Roussy-Levy syndrome is a form of CMT11 with the additional feature of rhythmic shaking (tremors). Dejerine-Sottas syndrome is a term sometimes used to describe a severe, early childhood form of Charcot-Marie-Tooth disease; it is also sometimes called type 3 (CMT3). Depending on the specific gene that is altered, this severe, early-onset form of the disorder may also be classified as CMT1 or CMT4. CMTX5 is also known as Rosenberg-Chutorian syndrome.
Last Evaluated: Sep 25, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 10:62814098
Likely benign
Homo
Gene:
FKTN
Variant:
c.*2984C>T
rsID: rs886063332
Ref Allele: C
Alt Allele: T
Freq: 0.0096%rare
CADD: 3.779
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 9:105638248
Fukuyama congenital muscular dystrophy (FCMD) is characterized by hypotonia, symmetric generalized muscle weakness, and CNS migration disturbances that result in changes consistent with cobblestone (previously type II) lissencephaly with cerebral and cerebellar cortical dysplasia. Mild, typical, and severe phenotypes are recognized. Onset typically occurs in early infancy, with a poor suck, weak cry, and floppiness. Affected individuals have contractures of the hips, knees, and interphalangeal joints. Later features include myopathic facial appearance, pseudohypertrophy of the calves and forearms, motor and speech retardation, intellectual disability, seizures, ophthalmologic abnormalities including visual impairment and retinal dysplasia, and progressive cardiac involvement in individuals older than age ten years. Swallowing disturbance occurs in individuals with severe FCMD and in individuals older than age ten years, leading to recurrent aspiration pneumonia and death.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 9:105638248
Conflicting/Uncertain
Hetero
Gene:
DSP
Variant:
c.2121C>T
(p.Asn707=)
rsID: rs368590198
Ref Allele: C
Alt Allele: T
Freq: 0.0151%rare
CADD: 0.211
ClinVar Submissions (2)
Arrhythmogenic right ventricular cardiomyopathy (ARVC) – previously referred to as arrhythmogenic right ventricular dysplasia (ARVD) – is characterized by progressive fibrofatty replacement of the myocardium that predisposes to ventricular tachycardia and sudden death in young individuals and athletes. It primarily affects the right ventricle, and it may also involve the left ventricle. The presentation of disease is highly variable even within families, and some affected individuals may not meet established clinical criteria. The mean age at diagnosis is 31 years (±13; range: 4-64 years).
Last Evaluated: Jan 12, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 6:7572059
This syndrome has characteristics of woolly hair, palmoplantar keratoderma and dilated cardiomyopathy principally affecting the left ventricle. Only a few cases have been reported, all involving patients from Ecuador, India or Turkey. The woolly hair is present at birth and the palmoplantar keratoderma appears during the first year of life. The cardiac anomaly presents during childhood and is marked by dilation of the left ventricle accompanied by alterations in muscle contractility. The syndrome is transmitted as an autosomal recessive trait and is caused by mutations in the DSP gene (6p24) encoding desmoplakin, a protein involved in cell adhesion. The syndrome is similar to Naxos disease.
Last Evaluated: Jan 12, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 6:7572059
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jan 12, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 6:7572059
Likely benign
Hetero
Gene:
CYP11B1
Variant:
c.*1209C>T
rsID: rs757505651
Ref Allele: G
Alt Allele: A
Freq: 0.0191%rare
CADD: 1.538
ClinVar Submissions (1)
A genetic disorder characterized by defects in the synthesis of cortisol and/or aldosterone, resulting in hyperplasia of the adrenal cortical cells.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 8:142873164
Glucocorticoid-remediable aldosteronism is an autosomal dominant disorder characterized by hypertension, variable hyperaldosteronism, and abnormal adrenal steroid production, including 18-oxocortisol and 18-hydroxycortisol (Lifton et al., 1992). There is significant phenotypic heterogeneity, and some individuals never develop hypertension (Stowasser et al., 2000). Genetic Heterogeneity of Familial Hyperaldosteronism Familial hyperaldosteronism type II (HALD2; 605635) is caused by mutation in the CLCN2 gene (600570) on chromosome 3q27. Familial hyperaldosteronism type III (HALD3; 613677) is caused by mutation in the KCNJ5 gene (600734) on chromosome 11q24. Familial hyperaldosteronism type IV (HALD4; 617027) is caused by mutation in the CACNA1H gene (607904) on chromosome 16p13.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 8:142873164
Conflicting/Uncertain
Hetero
Gene:
DDOST
Variant:
c.945G>C
(p.Arg315=)
rsID: rs145327708
Ref Allele: C
Alt Allele: G
Freq: 0.0207%rare
CADD: 9.732
ClinVar Submissions (1)
A genetically heterogeneous group of heritable disorders resulting from defects in protein N-glycosylation.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 1:20653675
Conflicting/Uncertain
Hetero
Gene:
ARSB
Variant:
c.*212A>G
rsID: rs561718720
Ref Allele: T
Alt Allele: C
Freq: 0.0255%rare
CADD: 7.856
ClinVar Submissions (1)
Mucopolysaccharidosis type VI is an autosomal recessive lysosomal storage disorder resulting from a deficiency of arylsulfatase B. Clinical features and severity are variable, but usually include short stature, hepatosplenomegaly, dysostosis multiplex, stiff joints, corneal clouding, cardiac abnormalities, and facial dysmorphism. Intelligence is usually normal (Azevedo et al., 2004).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 5:78780185
Conflicting/Uncertain
Hetero
Gene:
FTO
Variant:
c.-186C>G
rsID: rs527438785
Ref Allele: C
Alt Allele: G
Freq: 0.0255%rare
CADD: 5.871
ClinVar Submissions (1)
Growth retardation, developmental delay, and facial dysmorphism (GDFD) is an autosomal recessive multiple congenital anomaly syndrome characterized by severe psychomotor retardation, poor overall growth, and dysmorphic facial features. Additional features may include cardiac malformations and deafness (summary by Daoud et al., 2016).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 16:53703999
Conflicting/Uncertain
Hetero
Gene:
POMC
Variant:
c.616G>T
(p.Glu206Ter)
rsID: rs202127120
Ref Allele: C
Alt Allele: A
Freq: 0.0263%rare
CADD: 39
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 18, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 2:25161269
Conflicting/Uncertain
Hetero
Gene:
KCNT1
Variant:
c.474G>A
(p.Ser158=)
rsID: rs139076605
Ref Allele: G
Alt Allele: A
Freq: 0.0263%rare
CADD: 0.888
ClinVar Submissions (4)
KCNT1-related epilepsy is most often associated with two phenotypes: epilepsy of infancy with migrating focal seizures (EIMFS) and autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). EIMFS is characterized by seizures, typically focal and asynchronous, beginning in the first six months of life with associated developmental plateau or regression. Autonomic manifestations (e.g., perioral cyanosis, flushing, apnea) are common. Seizures are intractable to multiple anticonvulsants and progress to become nearly continuous by age six to nine months. ADNFLE is characterized by clusters of nocturnal motor seizures that vary from simple arousals to hyperkinetic events with tonic or dystonic features. Individuals with KCNT1-related ADNFLE are more likely to develop seizures at a younger age, have cognitive comorbidity, and display psychiatric and behavioral problems than individuals with ADNFLE due to other causes. Less common seizure phenotypes in individuals with KCNT1-related epilepsy include West syndrome, Ohtahara syndrome, early myoclonic encephalopathy, leukodystrophy and/or leukoencephalopathy, focal epilepsy, and multifocal epilepsy. Additional neurologic features include hypotonia, microcephaly developing by age 12 months, strabismus, profound global developmental delay, and additional movement disorders. Other systemic manifestations including pulmonary hemorrhage caused by prominent systemic-to-pulmonary collateral arteries or cardiac arrhythmia have been reported.
Last Evaluated: Oct 31, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 9:135753976
Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is characterized by clusters of nocturnal motor seizures, which are often stereotyped and brief (5 seconds to 5 minutes). They vary from simple arousals from sleep to dramatic, often bizarre hyperkinetic events with tonic or dystonic features. Affected individuals may experience aura. Retained awareness during seizures is common. A minority of individuals experience daytime seizures. Onset ranges from infancy to adulthood. About 80% of individuals develop ADNFLE in the first two decades of life; mean age of onset is ten years. Clinical neurologic examination is normal and intellect is usually preserved, but reduced intellect, psychiatric comorbidity, or cognitive deficits may occur. Within a family, the manifestations of the disorder may vary considerably. ADNFLE is lifelong but not progressive. As an individual reaches middle age, attacks may become milder and less frequent.
Last Evaluated: Oct 31, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 9:135753976
Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as EPILEPSY or "seizure disorder."
Last Evaluated: Oct 31, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 9:135753976
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Oct 31, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 9:135753976
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Oct 31, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 9:135753976
Conflicting/Uncertain
Hetero
Gene:
TSC2
Variant:
c.3883+37C>T
rsID: rs45517315
Ref Allele: C
Alt Allele: T
Freq: 0.0287%rare
CADD: 10.13
ClinVar Submissions (1)
Tuberous sclerosis complex (TSC) involves abnormalities of the skin (hypomelanotic macules, confetti skin lesions, facial angiofibromas, shagreen patches, fibrous cephalic plaques, ungual fibromas); brain (subependymal nodules, cortical dysplasias, and subependymal giant cell astrocytomas [SEGAs], seizures, intellectual disability / developmental delay, psychiatric illness); kidney (angiomyolipomas, cysts, renal cell carcinomas); heart (rhabdomyomas, arrhythmias); and lungs (lymphangioleiomyomatosis [LAM], multifocal micronodular pneumonocyte hyperplasia). Central nervous system tumors are the leading cause of morbidity and mortality; renal disease is the second leading cause of early death.
Last Evaluated: -
Review Status: no assertion provided
Number of Submitters: 1
Clinical Significance: not provided
Assembly: GRCh38
Chromosome/Position: 16:2082541
Hetero
Gene:
CHIT1
Variant:
c.*124A>C
rsID: rs761217387
Ref Allele: T
Alt Allele: G
Freq: 0.0303%rare
CADD: 2.23
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 1:203216765
Conflicting/Uncertain
Hetero
Gene:
HSD3B7
Variant:
c.608G>A
(p.Arg203Lys)
rsID: rs201349611
Ref Allele: G
Alt Allele: A
Freq: 0.0303%rare
CADD: 18.82
ClinVar Submissions (1)
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jan 19, 2018
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 16:30986916
Conflicting/Uncertain
Hetero
Gene:
ACADM
Variant:
c.1091T>C
(p.Ile364Thr)
rsID: rs150710061
Ref Allele: T
Alt Allele: C
Freq: 0.0311%rare
CADD: 21.8
ClinVar Submissions (3)
Medium-chain acyl-coenzyme A dehydrogenase (MCAD) is one of the enzymes involved in mitochondrial fatty acid ß-oxidation, which fuels hepatic ketogenesis, a major source of energy once hepatic glycogen stores become depleted during prolonged fasting and periods of higher energy demands. In a typical clinical scenario, a previously healthy child with MCAD deficiency presents with hypoketotic hypoglycemia, vomiting, and lethargy triggered by a common illness. Seizures may occur. Hepatomegaly and liver disease are often present during an acute episode, which can quickly progress to coma and death. Children are normal at birth and – if not identified through newborn screening – typically present between ages three and 24 months; later presentation, even into adulthood, is possible. The prognosis is excellent once the diagnosis is established and frequent feedings are instituted to avoid any prolonged period of fasting.
Last Evaluated: May 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 1:75761267
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: May 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 1:75761267
Conflicting/Uncertain
Hetero
Gene:
COL6A2
Variant:
c.2517C>T
(p.Asp839=)
rsID: rs113002150
Ref Allele: C
Alt Allele: T
Freq: 0.0327%rare
CADD: 12.81
ClinVar Submissions (4)
Collagen type VI-related disorders represent a continuum of overlapping phenotypes with Bethlem myopathy at the mild end, Ullrich congenital muscular dystrophy (CMD) at the severe end, and two rare, less well-defined disorders – autosomal dominant limb-girdle muscular dystrophy and autosomal recessive myosclerosis myopathy – in between. Although Bethlem myopathy and Ullrich CMD were defined long before their molecular basis was known, they remain useful for clarification of prognosis and management. Bethlem myopathy, characterized by the combination of proximal muscle weakness and variable contractures, affects most frequently the long finger flexors, elbows, and ankles. Onset may be prenatal (characterized by decreased fetal movements), neonatal (hypotonia or torticollis), in early childhood (delayed motor milestones, muscle weakness, and contractures), or in adulthood (proximal weakness and Achilles tendon or long finger flexor contractures). Because of slow progression, more than two thirds of affected individuals over age 50 years rely on supportive means for outdoor mobility. Respiratory involvement is rare and appears to be related to more severe muscle weakness in later life. Ullrich CMD is characterized by congenital weakness and hypotonia, proximal joint contractures, and striking hyperlaxity of distal joints. Some affected children acquire the ability to walk independently; however, progression of the disease often results in later loss of ambulation. Early and severe respiratory involvement may require ventilatory support in the first or second decade of life.
Last Evaluated: Jul 03, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 21:46132009
Collagen type VI-related disorders represent a continuum of overlapping phenotypes with Bethlem myopathy at the mild end, Ullrich congenital muscular dystrophy (CMD) at the severe end, and two rare, less well-defined disorders – autosomal dominant limb-girdle muscular dystrophy and autosomal recessive myosclerosis myopathy – in between. Although Bethlem myopathy and Ullrich CMD were defined long before their molecular basis was known, they remain useful for clarification of prognosis and management. Bethlem myopathy, characterized by the combination of proximal muscle weakness and variable contractures, affects most frequently the long finger flexors, elbows, and ankles. Onset may be prenatal (characterized by decreased fetal movements), neonatal (hypotonia or torticollis), in early childhood (delayed motor milestones, muscle weakness, and contractures), or in adulthood (proximal weakness and Achilles tendon or long finger flexor contractures). Because of slow progression, more than two thirds of affected individuals over age 50 years rely on supportive means for outdoor mobility. Respiratory involvement is rare and appears to be related to more severe muscle weakness in later life. Ullrich CMD is characterized by congenital weakness and hypotonia, proximal joint contractures, and striking hyperlaxity of distal joints. Some affected children acquire the ability to walk independently; however, progression of the disease often results in later loss of ambulation. Early and severe respiratory involvement may require ventilatory support in the first or second decade of life.
Last Evaluated: Jul 03, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 21:46132009
A rare genetic non-dystrophic myopathy characterised by early diffuse, progressive muscle and joint contractures that result in severe limitation of movement of axial, proximal and distal joints, walking difficulties in early childhood and toe walking. Patients typically present thin, sclerotic muscles with a woody consistency, mild girdle and proximal limb weakness with moderate distal weakness and scoliosis. Muscle biopsy shows partial collagen VI deficiency at the myofibre basement membrane and absent collagen VI around most endomysial/perimysial capillaries. There is evidence the disease is caused by homozygous mutation in the COL6A2 gene.
Last Evaluated: Jul 03, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 21:46132009
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jul 03, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 21:46132009
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 03, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 21:46132009
Conflicting/Uncertain
Hetero
Gene:
HOGA1
Variant:
c.*289C>T
rsID: rs540860054
Ref Allele: C
Alt Allele: T
Freq: 0.035%rare
CADD: 0.588
ClinVar Submissions (1)
Primary hyperoxaluria is a rare condition characterized by recurrent kidney and bladder stones. The condition often results in end stage renal disease (ESRD), which is a life-threatening condition that prevents the kidneys from filtering fluids and waste products from the body effectively.Primary hyperoxaluria results from the overproduction of a substance called oxalate. Oxalate is filtered through the kidneys and excreted as a waste product in urine, leading to abnormally high levels of this substance in urine (hyperoxaluria). During its excretion, oxalate can combine with calcium to form calcium oxalate, a hard compound that is the main component of kidney and bladder stones. Deposits of calcium oxalate can damage the kidneys and other organs and lead to blood in the urine (hematuria), urinary tract infections, kidney damage, ESRD, and injury to other organs. Over time, kidney function decreases such that the kidneys can no longer excrete as much oxalate as they receive. As a result oxalate levels in the blood rise, and the substance gets deposited in tissues throughout the body (systemic oxalosis), particularly in bones and the walls of blood vessels. Oxalosis in bones can cause fractures.There are three types of primary hyperoxaluria that differ in their severity and genetic cause. In primary hyperoxaluria type 1, kidney stones typically begin to appear anytime from childhood to early adulthood, and ESRD can develop at any age. Primary hyperoxaluria type 2 is similar to type 1, but ESRD develops later in life. In primary hyperoxaluria type 3, affected individuals often develop kidney stones in early childhood, but few cases of this type have been described so additional signs and symptoms of this type are unclear.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 10:97611948
Conflicting/Uncertain
Hetero
Gene:
AGL
Variant:
c.1028G>A
(p.Arg343Gln)
rsID: rs137943515
Ref Allele: G
Alt Allele: A
Freq: 0.0358%rare
CADD: 29.9
ClinVar Submissions (2)
Glycogen storage disease type III (GSD III) is characterized by variable liver, cardiac muscle, and skeletal muscle involvement. GSD IIIa is the most common subtype, present in about 85% of affected individuals; it manifests with liver and muscle involvement. GSD IIIb, with liver involvement only, comprises about 15% of all GSD III. In infancy and early childhood, liver involvement presents as ketotic hypoglycemia, hepatomegaly, hyperlipidemia, and elevated hepatic transaminases. In adolescence and adulthood, liver disease becomes less prominent. Hypertrophic cardiomyopathy develops in the majority of those with GSD IIIa, usually during childhood. Its clinical significance ranges from asymptomatic in the majority to severe cardiac dysfunction, congestive heart failure, and (rarely) sudden death. Skeletal myopathy manifesting as weakness is not usually evident in childhood, but slowly progresses, typically becoming prominent in the third to fourth decade.
Last Evaluated: Jun 21, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 1:99874756
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jun 21, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 1:99874756
Conflicting/Uncertain
Hetero
Gene:
ATP13A2
Variant:
c.951C>T
(p.Cys317=)
rsID: rs148391179
Ref Allele: G
Alt Allele: A
Freq: 0.0398%rare
CADD: 19.08
ClinVar Submissions (2)
Parkinsonism refers to all clinical states characterized by tremor, muscle rigidity, slowed movement (bradykinesia) and often postural instability. Parkinson disease is the primary and most common form of parkinsonism. Psychiatric manifestations, which include depression and visual hallucinations, are common but not uniformly present. Dementia eventually occurs in at least 20% of cases. The most common sporadic form of Parkinson disease manifests around age 60; however, young-onset and even juvenile presentations are seen.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 1:17000099
Conflicting/Uncertain
Hetero
Gene:
KLHL40
Variant:
c.1738C>A
(p.Leu580Ile)
rsID: rs149980411
Ref Allele: C
Alt Allele: A
Freq: 0.0398%rare
CADD: 17.51
ClinVar Submissions (3)
Nemaline myopathy (referred to in this entry as NM) is characterized by weakness, hypotonia, and depressed or absent deep tendon reflexes. Muscle weakness is usually most severe in the face, the neck flexors, and the proximal limb muscles. The clinical classification defines six forms of NM, which are classified by onset and severity of motor and respiratory involvement: Severe congenital (neonatal) (16% of all individuals with NM). Amish NM. Intermediate congenital (20%). Typical congenital (46%). Childhood-onset (13%). Adult-onset (late-onset) (4%). Considerable overlap occurs among the forms. There are significant differences in survival between individuals classified as having severe, intermediate, and typical congenital NM. Severe neonatal respiratory disease and the presence of arthrogryposis multiplex congenita are associated with death in the first year of life. Independent ambulation before age 18 months is predictive of survival. Most children with typical congenital NM are eventually able to walk.
Last Evaluated: Dec 21, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 3:42690989
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Dec 21, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 3:42690989
Benign
Hetero
Gene:
TBX4
Variant:
c.1083G>C
(p.Val361=)
rsID: rs61739274
Ref Allele: G
Alt Allele: C
Freq: 0.0398%rare
CADD: 14.92
ClinVar Submissions (1)
A very rare benign bone dysplasia affecting skeletal structures of the lower limb and the pelvis. Less than 50 patients have been reported worldwide. The main clinical features include patellar aplasia or hypoplasia, associated with absent, delayed or irregular ossification of the ischiopubic junctions and/or the infra-acetabular axe-cut notches. Additional features found in the majority of reported patients include femur and foot anomalies. Craniofacial anomalies have been reported occasionally. Inherited in an autosomal dominant manner and is caused by mutations in the human TBX4 gene (chromosome 17q22). TBX4 mutations account for familial cases with a distinctive facial appearance and those without facial features.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 17:61482961
Likely benign
Hetero
Gene:
FECH
Variant:
c.*1915G>T
rsID: rs148459563
Ref Allele: C
Alt Allele: A
Freq: 0.047%rare
CADD: 3.035
ClinVar Submissions (1)
Erythropoietic protoporphyria (EPP) is characterized by cutaneous photosensitivity (usually beginning in infancy or childhood) that results in tingling, burning, pain, and itching within 30 minutes after exposure to sun or ultraviolet light and may be accompanied by swelling and redness. Symptoms (which may seem out of proportion to the visible skin lesions) may persist for hours or days after the initial phototoxic reaction. Photosensitivity remains for life. Multiple episodes of acute photosensitivity may lead to chronic changes of sun-exposed skin (lichenification, leathery pseudovesicles, grooving around the lips) and loss of lunulae of the nails. Approximately 20%-30% of individuals with EPP have some degree of liver dysfunction, which is typically mild with slight elevations of the liver enzymes. Up to 5% may develop more advanced liver disease which may be accompanied by motor neuropathy similar to that seen in the acute porphyrias.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 18:57548797
Likely benign
Hetero
Gene:
TGFB3
Variant:
c.293C>T
(p.Ser98Leu)
rsID: rs142047577
Ref Allele: G
Alt Allele: A
Freq: 0.0518%rare
CADD: 22.7
ClinVar Submissions (5)
Arrhythmogenic right ventricular cardiomyopathy (ARVC) – previously referred to as arrhythmogenic right ventricular dysplasia (ARVD) – is characterized by progressive fibrofatty replacement of the myocardium that predisposes to ventricular tachycardia and sudden death in young individuals and athletes. It primarily affects the right ventricle, and it may also involve the left ventricle. The presentation of disease is highly variable even within families, and some affected individuals may not meet established clinical criteria. The mean age at diagnosis is 31 years (±13; range: 4-64 years).
Last Evaluated: Apr 19, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 5
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 14:75980601
Last Evaluated: Apr 19, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 5
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 14:75980601
Left ventricular noncompaction is a heart (cardiac) muscle disorder that occurs when the lower left chamber of the heart (left ventricle), which helps the heart pump blood, does not develop correctly. Instead of the muscle being smooth and firm, the cardiac muscle in the left ventricle is thick and appears spongy. The abnormal cardiac muscle is weak and has an impaired ability to pump blood because it either cannot completely contract or it cannot completely relax. For the heart to pump blood normally, cardiac muscle must contract and relax fully.Some individuals with left ventricular noncompaction experience no symptoms at all; others have heart problems that can include sudden cardiac death. Additional signs and symptoms include abnormal blood clots, irregular heart rhythm (arrhythmia), a sensation of fluttering or pounding in the chest (palpitations), extreme fatigue during exercise (exercise intolerance), shortness of breath (dyspnea), fainting (syncope), swelling of the legs (lymphedema), and trouble laying down flat. Some affected individuals have features of other heart defects. Left ventricular noncompaction can be diagnosed at any age, from birth to late adulthood. Approximately two-thirds of individuals with left ventricular noncompaction develop heart failure.
Last Evaluated: Apr 19, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 5
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 14:75980601
Loeys-Dietz syndrome (LDS) is characterized by vascular findings (cerebral, thoracic, and abdominal arterial aneurysms and/or dissections), skeletal manifestations (pectus excavatum or pectus carinatum, scoliosis, joint laxity, arachnodactyly, talipes equinovarus, cervical spine malformation and/or instability), craniofacial features (widely spaced eyes, strabismus, bifid uvula / cleft palate, and craniosynostosis that can involve any sutures), and cutaneous findings (velvety and translucent skin, easy bruising, and dystrophic scars). Individuals with LDS are predisposed to widespread and aggressive arterial aneurysms and pregnancy-related complications including uterine rupture and death. Individuals with LDS can show a strong predisposition for allergic/inflammatory disease including asthma, eczema, and reactions to food or environmental allergens. There is also an increased incidence of gastrointestinal inflammation including eosinophilic esophagitis and gastritis or inflammatory bowel disease. Wide variation in the distribution and severity of clinical features can be seen in individuals with LDS, even among affected individuals within a family who have the same pathogenic variant.
Last Evaluated: Apr 19, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 5
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 14:75980601
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Apr 19, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 5
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 14:75980601
Conflicting/Uncertain
Hetero
Gene:
ITGA2
Variant:
c.*613C>T
rsID: rs537086711
Ref Allele: C
Alt Allele: T
Freq: 0.0645%rare
CADD: 0.898
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 5:53091212
Likely benign
Hetero
Gene:
COG5
Variant:
c.1130C>T
(p.Pro377Leu)
rsID: rs143773937
Ref Allele: G
Alt Allele: A
Freq: 0.0661%rare
CADD: 20.2
ClinVar Submissions (3)
A genetically heterogeneous group of heritable disorders resulting from defects in protein N-glycosylation.
Last Evaluated: Jan 16, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 7:107324511
COG5-congenital disorder of glycosylation (COG5-CDG, formerly known as congenital disorder of glycosylation type IIi) is an inherited condition that causes neurological problems and other abnormalities. The pattern and severity of this disorder's signs and symptoms vary among affected individuals.Individuals with COG5-CDG typically develop signs and symptoms of the condition during infancy. These individuals often have weak muscle tone (hypotonia) and delayed development. Other neurological features include moderate to severe intellectual disability, poor coordination, and difficulty walking. Some affected individuals never learn to speak. Other features of COG5-CDG include short stature, an unusually small head size (microcephaly), and distinctive facial features, which can include ears that are set low and rotated backward, a short neck with a low hairline in the back, and a prominent nose. Less commonly, affected individuals can have hearing loss caused by changes in the inner ear (sensorineural hearing loss), vision impairment, damage to the nerves that control bladder function (a condition called neurogenic bladder), liver disease, and joint deformities (contractures).
Last Evaluated: Jan 16, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 7:107324511
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jan 16, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 7:107324511
Conflicting/Uncertain
Hetero
Gene:
RNASEH2C
Variant:
c.417C>G
(p.Gly139=)
rsID: rs147021687
Ref Allele: G
Alt Allele: C
Freq: 0.0661%rare
CADD: 18.31
ClinVar Submissions (4)
Most characteristically, Aicardi-Goutières syndrome (AGS) manifests as an early-onset encephalopathy that usually, but not always, results in severe intellectual and physical disability. A subgroup of infants with AGS present at birth with abnormal neurologic findings, hepatosplenomegaly, elevated liver enzymes, and thrombocytopenia, a picture highly suggestive of congenital infection. Otherwise, most affected infants present at variable times after the first few weeks of life, frequently after a period of apparently normal development. Typically, they demonstrate the subacute onset of a severe encephalopathy characterized by extreme irritability, intermittent sterile pyrexias, loss of skills, and slowing of head growth. Over time, as many as 40% develop chilblain skin lesions on the fingers, toes, and ears. It is becoming apparent that atypical, sometimes milder, cases of AGS exist, and thus the true extent of the phenotype associated with pathogenic variants in the AGS-related genes is not yet known.
Last Evaluated: Jul 31, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 11:65720096
Most characteristically, Aicardi-Goutières syndrome (AGS) manifests as an early-onset encephalopathy that usually, but not always, results in severe intellectual and physical disability. A subgroup of infants with AGS present at birth with abnormal neurologic findings, hepatosplenomegaly, elevated liver enzymes, and thrombocytopenia, a picture highly suggestive of congenital infection. Otherwise, most affected infants present at variable times after the first few weeks of life, frequently after a period of apparently normal development. Typically, they demonstrate the subacute onset of a severe encephalopathy characterized by extreme irritability, intermittent sterile pyrexias, loss of skills, and slowing of head growth. Over time, as many as 40% develop chilblain skin lesions on the fingers, toes, and ears. It is becoming apparent that atypical, sometimes milder, cases of AGS exist, and thus the true extent of the phenotype associated with pathogenic variants in the AGS-related genes is not yet known.
Last Evaluated: Jul 31, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 11:65720096
Conflicting/Uncertain
Hetero
Gene:
FREM2
Variant:
c.*3645G>T
rsID: rs191682286
Ref Allele: G
Alt Allele: T
Freq: 0.0693%rare
CADD: 6.02
ClinVar Submissions (1)
Fraser syndrome is an autosomal recessive malformation disorder characterized by cryptophthalmos, syndactyly, and abnormalities of the respiratory and urogenital tract (summary by van Haelst et al., 2008). Genetic Heterogeneity of Fraser Syndrome Fraser syndrome-2 (FRASRS2) is caused by mutation in the FREM2 gene (608945) on chromosome 13q13, and Fraser syndrome-3 (FRASRS3) is caused by mutation in the GRIP1 gene (604597) on chromosome 12q14. See Bowen syndrome (211200) for a comparable but probably distinct syndrome of multiple congenital malformations.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 13:38884432
Conflicting/Uncertain
Hetero
Gene:
LAMC2
Variant:
c.*1617A>G
rsID: rs532073148
Ref Allele: A
Alt Allele: G
Freq: 0.0701%rare
CADD: 1.416
ClinVar Submissions (1)
Junctional epidermolysis bullosa (JEB) is characterized by fragility of the skin and mucous membranes, manifest by blistering with little or no trauma. Blistering may be severe and granulation tissue can form on the skin around the oral and nasal cavities, fingers and toes, and internally around the upper airway. Blisters generally heal with no significant scarring. Broad classification of JEB includes JEB generalized severe and JEB generalized intermediate. In JEB generalized severe, blisters are present at birth or become apparent in the neonatal period. Congenital malformations of the urinary tract and bladder may also occur. In JEB generalized intermediate, the phenotype may be mild with blistering localized to hands, feet, knees, and elbows with or without renal or ureteral involvement. Some individuals never blister after the newborn period. Additional features shared by JEB and the other major forms of epidermolysis bullosa (EB) include congenital localized absence of skin (aplasia cutis congenita), milia, nail dystrophy, scarring alopecia, hypotrichosis, pseudosyndactyly, and other contractures.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 1:183245017
Conflicting/Uncertain
Hetero
Gene:
ARFGEF2
Variant:
c.3892G>A
(p.Gly1298Ser)
rsID: rs139037316
Ref Allele: G
Alt Allele: A
Freq: 0.0733%rare
CADD: 26
ClinVar Submissions (4)
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Mar 05, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 20:49012058
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 05, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 20:49012058
Conflicting/Uncertain
Hetero
Gene:
COL17A1
Variant:
c.3206G>A
(p.Arg1069Gln)
rsID: rs147631156
Ref Allele: C
Alt Allele: T
Freq: 0.0741%rare
CADD: 1.72
ClinVar Submissions (1)
Junctional epidermolysis bullosa (JEB) is characterized by fragility of the skin and mucous membranes, manifest by blistering with little or no trauma. Blistering may be severe and granulation tissue can form on the skin around the oral and nasal cavities, fingers and toes, and internally around the upper airway. Blisters generally heal with no significant scarring. Broad classification of JEB includes JEB generalized severe and JEB generalized intermediate. In JEB generalized severe, blisters are present at birth or become apparent in the neonatal period. Congenital malformations of the urinary tract and bladder may also occur. In JEB generalized intermediate, the phenotype may be mild with blistering localized to hands, feet, knees, and elbows with or without renal or ureteral involvement. Some individuals never blister after the newborn period. Additional features shared by JEB and the other major forms of epidermolysis bullosa (EB) include congenital localized absence of skin (aplasia cutis congenita), milia, nail dystrophy, scarring alopecia, hypotrichosis, pseudosyndactyly, and other contractures.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 10:104037638
Conflicting/Uncertain
Hetero
Gene:
SEC63
Variant:
c.340-12_340-7delGTTTTTinsCCC
rsID: rs1554237221
Ref Allele: AAAAAC
Alt Allele: A
Freq: 0.0749%rare
ClinVar Submissions (2)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 14, 2014
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:107921916
Benign/Likely benign
Hetero
Gene:
SMARCA2
Variant:
c.1422G>A
(p.Gln474=)
rsID: rs144434753
Ref Allele: G
Alt Allele: A
Freq: 0.0812%rare
CADD: 10.77
ClinVar Submissions (1)
Nicolaides-Baraitser syndrome (NCBRS) is characterized by sparse scalp hair, prominence of the inter-phalangeal joints and distal phalanges due to decreased subcutaneous fat, characteristic coarse facial features, microcephaly, seizures, and developmental delay / intellectual disability. Seizures are of various types and can be difficult to manage. Developmental delay / intellectual disability (ID) is severe in nearly a half, moderate in a third, and mild in the remainder. Nearly a third never develop speech or language skills.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 9:2058365
Likely benign
Hetero
Gene:
YARS
Variant:
c.1015G>A
(p.Ala339Thr)
rsID: rs141323599
Ref Allele: C
Alt Allele: T
Freq: 0.0828%rare
CADD: 13.27
ClinVar Submissions (3)
Charcot-Marie-Tooth disease encompasses a group of disorders called hereditary sensory and motor neuropathies that damage the peripheral nerves. Peripheral nerves connect the brain and spinal cord to muscles and to sensory cells that detect sensations such as touch, pain, heat, and sound. Damage to the peripheral nerves that worsens over time can result in alteration or loss of sensation and wasting (atrophy) of muscles in the feet, legs, and hands.Charcot-Marie-Tooth disease usually becomes apparent in adolescence or early adulthood, but onset may occur anytime from early childhood through late adulthood. Symptoms of Charcot-Marie-Tooth disease vary in severity and age of onset even among members of the same family. Some people never realize they have the disorder because their symptoms are so mild, but most have a moderate amount of physical disability. A small percentage of people experience severe weakness or other problems which, in very rare cases, can be life-threatening. In most affected individuals, however, Charcot-Marie-Tooth disease does not affect life expectancy.Typically, the earliest symptoms of Charcot-Marie-Tooth disease result from muscle atrophy in the feet. Affected individuals may have foot abnormalities such as high arches (pes cavus), flat feet (pes planus), or curled toes (hammer toes). They often have difficulty flexing the foot or walking on the heel of the foot. These difficulties may cause a higher than normal step (steppage gait) and increase the risk of ankle injuries and tripping. As the disease worsens, muscles in the lower legs usually weaken, but leg and foot problems rarely require the use of a wheelchair.Affected individuals may also develop weakness in the hands, causing difficulty with daily activities such as writing, fastening buttons, and turning doorknobs. People with Charcot-Marie-Tooth disease typically experience a decreased sensitivity to touch, heat, and cold in the feet and lower legs, but occasionally feel aching or burning sensations. In rare cases, affected individuals have loss of vision or gradual hearing loss that sometimes leads to deafness.There are several types of Charcot-Marie-Tooth disease, which are differentiated by their effects on nerve cells and patterns of inheritance. Type 1 (CMT1) is characterized by abnormalities in myelin, the fatty substance that covers nerve cells, protecting them and helping to transmit nerve impulses. These abnormalities slow the transmission of nerve impulses and can affect the health of the nerve fiber. Type 2 (CMT2) is characterized by abnormalities in the fiber, or axon, that extends from a nerve cell body to muscles or to sense organs. These abnormalities reduce the strength of the nerve impulse. In forms of Charcot-Marie-Tooth disease classified as intermediate type, the nerve impulses are both slowed and reduced in strength, probably due to abnormalities in both myelin and axons. Type 4 (CMT4) is distinguished from the other types by its pattern of inheritance; it can affect either the axons or the myelin. Type X Charcot-Marie-Tooth disease (CMTX) is caused by mutations in genes on the X chromosome, one of the two sex chromosomes. Within the various types of Charcot-Marie-Tooth disease, subtypes (such as CMT1A, CMT1B, CMT2A, CMT4A, and CMTX1) indicate different genetic causes.Sometimes other, historical names are used to refer to particular forms of Charcot-Marie-Tooth disease. For example, Roussy-Levy syndrome is a form of CMT11 with the additional feature of rhythmic shaking (tremors). Dejerine-Sottas syndrome is a term sometimes used to describe a severe, early childhood form of Charcot-Marie-Tooth disease; it is also sometimes called type 3 (CMT3). Depending on the specific gene that is altered, this severe, early-onset form of the disorder may also be classified as CMT1 or CMT4. CMTX5 is also known as Rosenberg-Chutorian syndrome.
Last Evaluated: Jan 05, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:32782431
Last Evaluated: Jan 05, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:32782431
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jan 05, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:32782431
Benign/Likely benign
Hetero
Gene:
SLC10A2
Variant:
c.194C>T
(p.Pro65Leu)
rsID: rs112657170
Ref Allele: G
Alt Allele: A
Freq: 0.0995%rare
CADD: 29.9
ClinVar Submissions (1)
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jul 27, 2018
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 13:103066056
Conflicting/Uncertain
Hetero
Gene:
MYO5A
Variant:
c.3136G>A
(p.Val1046Met)
rsID: rs56132571
Ref Allele: C
Alt Allele: T
Freq: 0.0995%rare
CADD: 15.77
ClinVar Submissions (2)
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Feb 28, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 15:52367055
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Feb 28, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 15:52367055
Conflicting/Uncertain
Hetero
Gene:
TTN
Variant:
c.2764C>T
(p.Arg922Cys)
rsID: rs72647862
Ref Allele: G
Alt Allele: A
Freq: 0.1075%rare
CADD: 16.15
ClinVar Submissions (5)
Last Evaluated: Nov 30, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:178784081
Last Evaluated: Nov 30, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:178784081
Limb-girdle muscular dystrophy is a term for a group of diseases that cause weakness and wasting of the muscles in the arms and legs. The muscles most affected are those closest to the body (proximal muscles), specifically the muscles of the shoulders, upper arms, pelvic area, and thighs.The severity, age of onset, and features of limb-girdle muscle dystrophy vary among the many subtypes of this condition and may be inconsistent even within the same family. Signs and symptoms may first appear at any age and generally worsen with time, although in some cases they remain mild.In the early stages of limb-girdle muscular dystrophy, affected individuals may have an unusual walking gait, such as waddling or walking on the balls of their feet, and may also have difficulty running. They may need to use their arms to press themselves up from a squatting position because of their weak thigh muscles. As the condition progresses, people with limb-girdle muscular dystrophy may eventually require wheelchair assistance.Muscle wasting may cause changes in posture or in the appearance of the shoulder, back, and arm. In particular, weak shoulder muscles tend to make the shoulder blades (scapulae) "stick out" from the back, a sign known as scapular winging. Affected individuals may also have an abnormally curved lower back (lordosis) or a spine that curves to the side (scoliosis). Some develop joint stiffness (contractures) that can restrict movement in their hips, knees, ankles, or elbows. Overgrowth (hypertrophy) of the calf muscles occurs in some people with limb-girdle muscular dystrophy.Weakening of the heart muscle (cardiomyopathy) occurs in some forms of limb-girdle muscular dystrophy. Some affected individuals experience mild to severe breathing problems related to the weakness of muscles needed for breathing. In some cases, the breathing problems are severe enough that affected individuals need to use a machine to help them breathe (mechanical ventilation).Intelligence is generally unaffected in limb-girdle muscular dystrophy; however, developmental delay and intellectual disability have been reported in rare forms of the disorder.
Last Evaluated: Nov 30, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:178784081
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Nov 30, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:178784081
Likely benign
Hetero
Gene:
RNF125
Variant:
c.387A>G
(p.Leu129=)
rsID: rs144268137
Ref Allele: A
Alt Allele: G
Freq: 0.1091%rare
CADD: 7.142
ClinVar Submissions (1)
Tenorio syndrome is characterized by overgrowth, macrocephaly, and intellectual disability (ID). Some patients may have mild hydrocephaly, hypoglycemia, and inflammatory diseases resembling Sjogren syndrome (270150) (summary by Tenorio et al., 2014).
Last Evaluated: Jun 13, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 18:32042247
Benign
Hetero
Gene:
LAMA2
Variant:
c.6161A>G
(p.Gln2054Arg)
rsID: rs56035053
Ref Allele: A
Alt Allele: G
Freq: 0.1179%rare
CADD: 18.72
ClinVar Submissions (8)
The clinical manifestations of LAMA2-related muscular dystrophy (LAMA2 MD) range from severe, early-onset congenital muscular dystrophy (CMD) – referred to as early-onset LAMA2-related muscular dystrophy (LAMA2 MD) in this GeneReview – to mild, later childhood-onset limb-girdle type muscular dystrophy – referred to here as late-onset LAMA2-related muscular dystrophy (LAMA2 MD). Children with early-onset LAMA2 MD have profound hypotonia with muscle weakness evident at birth or within the first six months of life, poor spontaneous movements with contractures of the large joints, and weak cry often associated with respiratory failure. Feeding difficulties with failure to thrive, aspiration, and recurrent chest infections are typical. Progressive scoliosis starting in childhood is common. Seizures and, less often, cardiac involvement can occur. Typically, individuals with early-onset LAMA2 MD do not achieve independent ambulation. Intellect is usually normal. Those with limb-girdle type muscular dystrophy have later onset of proximal muscle weakness and delayed motor milestones, but achieve independent ambulation; they may develop a rigid spine syndrome with joint contractures. Progressive respiratory insufficiency and scoliosis can occur.
Last Evaluated: Jun 20, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 8
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 6:129440891
Merosin-deficient congenital muscular dystrophy is an autosomal recessive form of muscular dystrophy characterized by muscle weakness apparent at birth or in the first 6 months of life. Patients show hypotonia, poor suck and cry, and delayed motor development; most never achieve independent ambulation. Most patients also have periventricular white matter abnormalities on brain imaging, but mental retardation and/or seizures occur only rarely (summary by Xiong et al., 2015).
Last Evaluated: Jun 20, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 8
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 6:129440891
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jun 20, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 8
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 6:129440891
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 20, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 8
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 6:129440891
Conflicting/Uncertain
Hetero
Gene:
SHANK2
Variant:
c.3387G>A
(p.Met1129Ile)
rsID: rs140134890
Ref Allele: C
Alt Allele: T
Freq: 0.125%rare
CADD: 13.05
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 22, 2015
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 11:70473268
Likely benign
Hetero
Gene:
ARHGAP31
Variant:
c.662C>T
(p.Pro221Leu)
rsID: rs751793
Ref Allele: C
Alt Allele: T
Freq: 0.1338%rare
CADD: 10.31
ClinVar Submissions (2)
Adams-Oliver syndrome (AOS) is characterized by aplasia cutis congenita (ACC) of the scalp and terminal transverse limb defects (TTLD). ACC lesions usually occur in the midline of the parietal or occipital regions, but can also occur on the abdomen or limbs. At birth, an ACC lesion may already have the appearance of a healed scar. ACC lesions less than 5 cm often involve only the skin and almost always heal over a period of months; larger lesions are more likely to involve the skull and possibly the dura, and are at greater risk for complications, which can include infection, hemorrhage, or thrombosis, and can result in death. The limb defects range from mild (unilateral or bilateral short distal phalanges) to severe (complete absence of all toes or fingers, feet or hands, or more, often resembling an amputation). The lower extremities are almost always more severely affected than the upper extremities. Additional major features frequently include cardiovascular malformations/dysfunction (23%), brain anomalies, and less frequently renal, liver, and eye anomalies.
Last Evaluated: Jan 12, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 3:119383206
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jan 12, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 3:119383206
Likely benign
Hetero
Gene:
NDE1
Variant:
c.-773G>A
rsID: rs376603273
Ref Allele: G
Alt Allele: A
Freq: 0.1346%rare
CADD: 20.9
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 16:15643320
Conflicting/Uncertain
Hetero
Gene:
SH3BP2
Variant:
c.*162G>A
rsID: rs61791176
Ref Allele: G
Alt Allele: A
Freq: 0.1354%rare
CADD: 8.351
ClinVar Submissions (1)
Cherubism is a childhood-onset, autoinflammatory bone disease characterized by bilateral and symmetric proliferative fibroosseous lesions limited to the mandible and maxilla. The enlargement is usually symmetric in nature. The phenotype ranges from no clinical manifestations to severe mandibular and maxillary overgrowth with respiratory, vision, speech, and swallowing problems. In most affected persons, teeth are displaced, unerupted, unformed, or absent, or may appear to be floating in cystlike spaces; malocclusion, premature exfoliation of deciduous teeth, and root resorption have also been reported. The course and duration of the active process of bone destruction varies between affected individuals; the onset is usually in early childhood, and typically new lesions can occur until puberty. Regression of the lesions occurs as they become filled with bone and remodel during the second and third decade of life. By age 30 years, the facial abnormalities associated with cherubism are not usually recognizable and residual deformity of the jaws is rare. Typically, cherubism is an isolated benign condition; the affected person has normal intellectual skills and is without other physical anomalies.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 4:2833996
Likely benign
Hetero
Gene:
GABRA1
Variant:
c.-449G>C
rsID: rs190043578
Ref Allele: G
Alt Allele: C
Freq: 0.141%rare
CADD: 0.671
ClinVar Submissions (1)
Juvenile myoclonic epilepsy is a subtype of idiopathic generalized epilepsy (EIG; see 600669) affecting up to 26% of all individuals with EIG. Individuals with JME have afebrile seizures only, with onset in adolescence of myoclonic jerks. Myoclonic jerks occur usually in the morning (Janz and Durner, 1997). Genetic Heterogeneity of Juvenile Myoclonic Seizures Susceptibility to EJM can be conferred by variation in several other genes: EJM5 (611136), by variation in the GABRA1 gene (137160) on 5q34; EJM6 (see 607682), by variation in the CACNB4 gene (601949) on 2q23; EJM7 (see 613060), by variation in the GABRD gene (137163) on 1p36; EJM8 (see 607628), by variation in the CLCN2 gene (600570) on 3q27; and EJM10 (617924), by variation in the ICK gene (612325) on chromosome 6p12. In addition, EJM loci have been identified by linkage analysis: EJM2 (see 604827) on 15q14, EJM3 (608816) on 6p21, EJM4 (611364) on 5q12-q14, and EJM9 (614280) on 2q33-q36.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 5:161847210
Conflicting/Uncertain
Hetero
Gene:
POLR3A
Variant:
c.*135G>T
rsID: rs531659725
Ref Allele: C
Alt Allele: A
Freq: 0.1473%rare
CADD: 0.261
ClinVar Submissions (1)
POLR3-related leukodystrophy, a hypomyelinating leukodystrophy with specific features on brain MRI, is characterized by varying combinations of four major clinical findings: Neurologic dysfunction, typically predominated by motor dysfunction (progressive cerebellar dysfunction, and to a lesser extent extrapyramidal [i.e., dystonia], pyramidal [i.e., spasticity] and cognitive dysfunctions). Abnormal dentition (delayed dentition, hypodontia, oligodontia, and abnormally placed or shaped teeth). Endocrine abnormalities such as short stature (in ~50% of individuals) with or without growth hormone deficiency, and more commonly, hypogonadotropic hypogonadism manifesting as delayed, arrested, or absent puberty. Ocular abnormality in the form of myopia, typically progressing over several years and becoming severe. POLR3-related leukodystrophy and 4H leukodystrophy are the two recognized terms for five previously described overlapping clinical phenotypes (initially described as distinct entities before their molecular basis was known). These include: Hypomyelination, hypodontia, hypogonadotropic hypogonadism (4H syndrome); Ataxia, delayed dentition, and hypomyelination (ADDH); Tremor-ataxia with central hypomyelination (TACH); Leukodystrophy with oligodontia (LO); Hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum (HCAHC). Age of onset is typically in early childhood but later-onset cases have also been reported. An infant with Wiedemann-Rautenstrauch syndrome (neonatal progeroid syndrome) was recently reported to have pathogenic variants in POLR3A on exome sequencing. Confirmation of this as a very severe form of POLR3-related leukodystrophy awaits replication in other individuals with a clinical diagnosis of Wiedemann-Rautenstrauch syndrome.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 10:77977343
Conflicting/Uncertain
Hetero
Gene:
OGDHL
Variant:
c.886A>T
(p.Met296Leu)
rsID: rs150231967
Ref Allele: T
Alt Allele: A
Freq: 0.1481%rare
CADD: 26.2
ClinVar Submissions (1)
Diseases that are caused by genetic mutations present during embryo or fetal development, although they may be observed later in life. The mutations may be inherited from a parent's genome or they may be acquired in utero.
Last Evaluated: Jan 16, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 10:49750849
Likely benign
Hetero
Gene:
POLR3A
Variant:
c.*136C>T
rsID: rs568729735
Ref Allele: G
Alt Allele: A
Freq: 0.1481%rare
CADD: 0.725
ClinVar Submissions (1)
POLR3-related leukodystrophy, a hypomyelinating leukodystrophy with specific features on brain MRI, is characterized by varying combinations of four major clinical findings: Neurologic dysfunction, typically predominated by motor dysfunction (progressive cerebellar dysfunction, and to a lesser extent extrapyramidal [i.e., dystonia], pyramidal [i.e., spasticity] and cognitive dysfunctions). Abnormal dentition (delayed dentition, hypodontia, oligodontia, and abnormally placed or shaped teeth). Endocrine abnormalities such as short stature (in ~50% of individuals) with or without growth hormone deficiency, and more commonly, hypogonadotropic hypogonadism manifesting as delayed, arrested, or absent puberty. Ocular abnormality in the form of myopia, typically progressing over several years and becoming severe. POLR3-related leukodystrophy and 4H leukodystrophy are the two recognized terms for five previously described overlapping clinical phenotypes (initially described as distinct entities before their molecular basis was known). These include: Hypomyelination, hypodontia, hypogonadotropic hypogonadism (4H syndrome); Ataxia, delayed dentition, and hypomyelination (ADDH); Tremor-ataxia with central hypomyelination (TACH); Leukodystrophy with oligodontia (LO); Hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum (HCAHC). Age of onset is typically in early childhood but later-onset cases have also been reported. An infant with Wiedemann-Rautenstrauch syndrome (neonatal progeroid syndrome) was recently reported to have pathogenic variants in POLR3A on exome sequencing. Confirmation of this as a very severe form of POLR3-related leukodystrophy awaits replication in other individuals with a clinical diagnosis of Wiedemann-Rautenstrauch syndrome.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 10:77977342
Conflicting/Uncertain
Hetero
Gene:
XPNPEP3
Variant:
c.590-8A>G
rsID: rs143719656
Ref Allele: A
Alt Allele: G
Freq: 0.1505%rare
CADD: 3.935
ClinVar Submissions (3)
Last Evaluated: Oct 20, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 22:40886305
The nephronophthisis (NPH) phenotype is characterized by reduced renal concentrating ability, chronic tubulointerstitial nephritis, cystic renal disease, and progression to end-stage renal disease (ESRD) before age 30 years. Three age-based clinical subtypes are recongnized: infantile, juvenile, and adolescent/adult. Infantile NPH can present in utero with oligohydramnios sequence (limb contractures, pulmonary hypoplasia and facial dysmorphisms) or postnatally with renal manifestations that progress to ESRD before age 3 years. Juvenile NPH, the most prevalent subtype, typically presents with polydipsia and polyuria, growth retardation, chronic iron-resistant anemia, or other findings related to chronic kidney disease (CKD). Hypertension is typically absent due to salt wasting. ESRD develops at a median age of 13 years. Ultrasound findings are increased echogenicity, reduced corticomedullary differentiation, and renal cysts (in 50% of affected individuals). Histologic findings include tubulointerstitial fibrosis, thickened and disrupted tubular basement membrane, sporadic corticomedullary cysts, and normal or reduced kidney size. Adolescent/ adult NPH is clinically similar to juvenile NPH, but ESRD develops at a median age of 19 years. Within a subtype inter- and intrafamilial variability in rate of progression to ESRD is considerable. Approximately 80%-90% of individuals with the NPH phenotype have no extrarenal features (i.e., they have isolated NPH); ~10%-20% have extrarenal manifestations that constitute a recognizable syndrome (e.g., Joubert syndrome, Bardet-Biedl syndrome, Jeune syndrome and related skeletal disorders, Meckel-Gruber syndrome, Senior-Løken syndrome, Leber congenital amaurosis, COACH syndrome, and oculomotor apraxia, Cogan type).
Last Evaluated: Oct 20, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 22:40886305
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Oct 20, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 22:40886305
Conflicting/Uncertain
Hetero
Gene:
TSC2
Variant:
c.1276C>T
(p.Leu426=)
rsID: rs45478593
Ref Allele: C
Alt Allele: T
Freq: 0.1521%rare
CADD: 3.721
ClinVar Submissions (9)
The condition of a pattern of malignancies within a family, but not every individual's necessarily having the same neoplasm. Characteristically the tumor tends to occur at an earlier than average age, individuals may have more than one primary tumor, the tumors may be multicentric, usually more than 25 percent of the individuals in direct lineal descent from the proband are affected, and the cancer predisposition in these families behaves as an autosomal dominant trait with about 60 percent penetrance.
Last Evaluated: Jan 09, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 9
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 16:2062515
Tuberous sclerosis complex (TSC) involves abnormalities of the skin (hypomelanotic macules, confetti skin lesions, facial angiofibromas, shagreen patches, fibrous cephalic plaques, ungual fibromas); brain (subependymal nodules, cortical dysplasias, and subependymal giant cell astrocytomas [SEGAs], seizures, intellectual disability / developmental delay, psychiatric illness); kidney (angiomyolipomas, cysts, renal cell carcinomas); heart (rhabdomyomas, arrhythmias); and lungs (lymphangioleiomyomatosis [LAM], multifocal micronodular pneumonocyte hyperplasia). Central nervous system tumors are the leading cause of morbidity and mortality; renal disease is the second leading cause of early death.
Last Evaluated: Jan 09, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 9
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 16:2062515
Tuberous sclerosis complex (TSC) involves abnormalities of the skin (hypomelanotic macules, confetti skin lesions, facial angiofibromas, shagreen patches, fibrous cephalic plaques, ungual fibromas); brain (subependymal nodules, cortical dysplasias, and subependymal giant cell astrocytomas [SEGAs], seizures, intellectual disability / developmental delay, psychiatric illness); kidney (angiomyolipomas, cysts, renal cell carcinomas); heart (rhabdomyomas, arrhythmias); and lungs (lymphangioleiomyomatosis [LAM], multifocal micronodular pneumonocyte hyperplasia). Central nervous system tumors are the leading cause of morbidity and mortality; renal disease is the second leading cause of early death.
Last Evaluated: Jan 09, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 9
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 16:2062515
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jan 09, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 9
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 16:2062515
Benign/Likely benign
Hetero
Gene:
ADGRV1
Variant:
c.1522A>C
(p.Ile508Leu)
rsID: rs61744480
Ref Allele: A
Alt Allele: C
Freq: 0.1553%rare
CADD: 24.4
ClinVar Submissions (3)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Nov 10, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 5:90629222
Benign/Likely benign
Hetero
Gene:
TLR3
Variant:
c.889C>G
(p.Leu297Val)
rsID: rs35311343
Ref Allele: C
Alt Allele: G
Freq: 0.1569%rare
CADD: 23.4
ClinVar Submissions (2)
Herpes simplex virus (HSV)-1 is most often associated with infection of the oral mucosa. Primary infection is most commonly asymptomatic, but it may lead to symptoms usually involving the mucosa and skin. Following replication at the infection site, HSV-1 enters the epithelial endings of sensory neurons and travels up the trigeminal cranial nerves to the trigeminal ganglia, where latent infection is established. Reactivation of HSV-1, usually in the form of herpes labialis (cold sores), may occur in 20 to 40% of the population. HSV-1 seroprevalence is high, with over 85% of adults between the ages of 20 and 40 years infected. HSV-1 rarely infects the central nervous system (CNS), resulting in herpes simplex encephalitis (HSE), with an incidence of 2 to 4 per 1,000,000 people per year. In HSE, HSV-1 invades and replicates in neurons and glial cells, where focal necrotizing infections occur, primarily affecting the temporal and subfrontal regions of the brain. Untreated, HSE is fatal in at least 70% of cases, although the mortality and morbidity have been drastically reduced with antiviral therapy. Approximately one-third of all HSE cases are due to primary infections, and 30% of all HSE cases occur in children under the age of 20 years. Among children, HSE peaks between 3 months and 3 years of age, coinciding with the time of primary infection. In a subset of children, HSE results from a series of monogenic primary immunodeficiencies that impair UNC93B1- and TLR3 (603029)-dependent production of IFNA (147660)/IFNB (147640) and IFNG (147570) in the CNS (summary by Sancho-Shimizu et al., 2007). Genetic Heterogeneity of Susceptibility to Acute Infection-Induced Encephalopathy, including Herpes Simplex Encephalitis (HSE) For other forms of susceptibility to acute infection-induced encephalopathy, see herpes-specific IIAE2 (613002), caused by mutation in the TLR3 gene (603029) on chromosome 4q35; IIAE3 (608033), caused by mutation in the RANBP2 gene (601181) on chromosome 2q12; IIAE4 (614212), caused by mutation in the CPT2 gene (600650) on chromosome 1p32; herpes-specific IIAE5 (614849), caused by mutation in the TRAF3 gene (601896) on chromosome 14q32; herpes-specific IIAE6 (614850), caused by mutation in the TICAM1 gene (607601) on chromosome 19p13; herpes-specific IIAE7 (616532), caused by mutation in the IRF3 gene (603734) on chromosome 19q13; and herpes-specific IIAE8 (617900), caused by mutation in the TBK1 gene (604834) on chromosome 12q14.
Last Evaluated: Aug 08, 2018
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 4:186082575
OMIM Allelic Variant: 603029.0007
Herpes simplex encephalitis (HSE) is a severe viral infection of the central nervous system (CNS) resulting most commonly from infection with HSV-1 and occasionally by HSV-2. The disease peaks in childhood between 3 months and 3 years of age, although later onset can also occur, and affected individuals usually have neurologic sequelae, including seizures and cognitive or motor impairment. Some individuals may have recurrences of an acute episode of HSE; however, patients have no clear susceptibility to infection to other viruses. The virus gains entry to the CNS through a neuronal route via the trigeminal or olfactory nerves, not via the blood. Replication of this enveloped double-stranded DNA (dsDNA) virus involves the production and accumulation of RNA species, including dsRNA, which are recognized by the intracellular TLR3 signaling pathway. The susceptibility to HSV in particular appears to result from impaired TLR3-dependent interferon production by nonhematopoietic cells that reside within the CNS (review by Zhang et al., 2013; summary by Mork et al., 2015). For a general phenotypic description of herpes simplex encephalitis and a discussion of genetic heterogeneity of acute infection-induced encephalopathy, see 610551.
Last Evaluated: Aug 08, 2018
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 4:186082575
OMIM Allelic Variant: 603029.0007
Conflicting/Uncertain
Hetero
Gene:
SKIV2L
Variant:
c.3666G>A
(p.Leu1222=)
rsID: rs142860816
Ref Allele: G
Alt Allele: A
Freq: 0.1664%rare
CADD: 12.48
ClinVar Submissions (1)
Although the spectrum of phenotypic expression in trichohepatoenteric syndrome (THES) is broad, the characteristic features include intrauterine growth retardation, woolly hair, facial dysmorphism, intractable diarrhea in infancy requiring total parenteral nutrition, and immunodepression. Hepatic involvement contributes to the poor prognosis of affected patients (summary by Fabre et al., 2007). Genetic Heterogeneity of Trichohepatoenteric Syndrome Trichohepatoenteric syndrome-2 (THES2; 614602) is caused by mutation in the SKIV2L gene (600478) on chromosome 6p21.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 6:31969640
Conflicting/Uncertain
Hetero
Gene:
CFB
Variant:
c.724A>C
(p.Ile242Leu)
rsID: rs144812066
Ref Allele: A
Alt Allele: C
Freq: 0.1696%rare
CADD: 16.14
ClinVar Submissions (1)
Hemolytic-uremic syndrome (HUS) is characterized by hemolytic anemia, thrombocytopenia, and renal failure caused by platelet thrombi in the microcirculation of the kidney and other organs. The onset of atypical HUS (aHUS) ranges from the neonatal period to adulthood. Genetic aHUS accounts for an estimated 60% of all aHUS. Individuals with genetic aHUS frequently experience relapse even after complete recovery following the presenting episode; 60% of genetic aHUS progresses to end-stage renal disease (ESRD).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 6:31947807
A nonspecific term denoting degeneration of the retinal pigment epithelium and/or retinal photoreceptor cells of the macula lutea.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 6:31947807
Likely benign
Hetero
Gene:
CDC73
Variant:
c.*12C>A
rsID: rs193025205
Ref Allele: C
Alt Allele: A
Freq: 0.1704%rare
CADD: 6.543
ClinVar Submissions (4)
The spectrum of CDC73-related disorders includes the following phenotypes: Hyperparathyroidism-jaw tumor (HPT-JT) syndrome. Primary hyperparathyroidism, the main finding of HPT-JT syndrome, occurs in up to 95% of affected individuals; onset is typically in late adolescence or early adulthood. HPT-JT-associated primary hyperparathyroidism is usually caused by a single parathyroid adenoma. In approximately 10%-15% of individuals, primary hyperparathyroidism is caused by parathyroid carcinoma. Ossifying fibromas of the mandible or maxilla, also known as cementifying fibromas and cemento-ossifying fibromas, occur in 30%-40% of individuals with HPT-JT syndrome. Although benign, these tumors can be locally aggressive and may continue to enlarge if not treated. Approximately 20% of individuals with HPT-JT syndrome have kidney lesions, most commonly cysts; renal hamartomas and (more rarely) Wilms tumor have also been reported. Benign and malignant uterine tumors appear to be common in women with HPT-JT syndrome. Parathyroid carcinoma. Most parathyroid carcinomas are functional, resulting in hyperparathyroidism and a high serum calcium level; however, non-functioning parathyroid carcinomas are also rarely described in individuals with a CDC73-related disorder. A germline CDC73 pathogenic variant has been identified in 20%-29% of individuals with apparently sporadic parathyroid carcinoma. Familial isolated hyperparathyroidism (FIHP). FIHP is characterized by primary hyperparathyroidism without other associated syndromic features. Individuals with CDC73-related FIHP tend to have a more severe clinical presentation and younger age of onset than individuals with FIHP in whom a CDC73 pathogenic variant has not been identified.
Last Evaluated: Jun 02, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:193250724
Last Evaluated: Jun 02, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:193250724
The spectrum of CDC73-related disorders includes the following phenotypes: Hyperparathyroidism-jaw tumor (HPT-JT) syndrome. Primary hyperparathyroidism, the main finding of HPT-JT syndrome, occurs in up to 95% of affected individuals; onset is typically in late adolescence or early adulthood. HPT-JT-associated primary hyperparathyroidism is usually caused by a single parathyroid adenoma. In approximately 10%-15% of individuals, primary hyperparathyroidism is caused by parathyroid carcinoma. Ossifying fibromas of the mandible or maxilla, also known as cementifying fibromas and cemento-ossifying fibromas, occur in 30%-40% of individuals with HPT-JT syndrome. Although benign, these tumors can be locally aggressive and may continue to enlarge if not treated. Approximately 20% of individuals with HPT-JT syndrome have kidney lesions, most commonly cysts; renal hamartomas and (more rarely) Wilms tumor have also been reported. Benign and malignant uterine tumors appear to be common in women with HPT-JT syndrome. Parathyroid carcinoma. Most parathyroid carcinomas are functional, resulting in hyperparathyroidism and a high serum calcium level; however, non-functioning parathyroid carcinomas are also rarely described in individuals with a CDC73-related disorder. A germline CDC73 pathogenic variant has been identified in 20%-29% of individuals with apparently sporadic parathyroid carcinoma. Familial isolated hyperparathyroidism (FIHP). FIHP is characterized by primary hyperparathyroidism without other associated syndromic features. Individuals with CDC73-related FIHP tend to have a more severe clinical presentation and younger age of onset than individuals with FIHP in whom a CDC73 pathogenic variant has not been identified.
Last Evaluated: Jun 02, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:193250724
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jun 02, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:193250724
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 02, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:193250724
Likely benign
Hetero
Gene:
LMBR1
Variant:
c.*2926G>C
rsID: rs148658727
Ref Allele: C
Alt Allele: G
Freq: 0.1752%rare
CADD: 0.113
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:156681152
Likely benign
Hetero
Gene:
AGXT
Variant:
c.836T>C
(p.Ile279Thr)
rsID: rs140992177
Ref Allele: T
Alt Allele: C
Freq: 0.1864%rare
CADD: 23.8
ClinVar Submissions (2)
Primary hyperoxaluria type 1 (PH1) is caused by a deficiency of the liver peroxisomal enzyme alanine:glyoxylate-aminotransferase (AGT), which catalyzes the conversion of glyoxylate to glycine. When AGT activity is absent, glyoxylate is converted to oxalate, which forms insoluble calcium oxalate crystals that accumulate in the kidney and other organs. Individuals with PH1 are at risk for recurrent nephrolithiasis (deposition of calcium oxalate in the renal pelvis / urinary tract), nephrocalcinosis (deposition of calcium oxalate in the renal parenchyma), or end-stage renal disease (ESRD). Age at onset of symptoms ranges from infancy to the sixth decade. Approximately 10% of affected individuals present in infancy or early childhood with nephrocalcinosis, with or without nephrolithiasis, and failure to thrive related to renal failure. The majority of individuals with PH1 present in childhood or early adolescence, usually with symptomatic nephrolithiasis and normal or reduced kidney function. The remainder of affected individuals present in adulthood with recurrent renal stones and a mild-to-moderate reduction in kidney function. The natural history of untreated PH1 is one of progressive decline in renal function as a result of calcium oxalate deposits in kidney tissue and complications of nephrolithiasis (e.g., obstruction and infection) with eventual progression to oxalosis (widespread tissue deposition of calcium oxalate) and death from ESRD and/or complications of oxalosis.
Last Evaluated: Apr 15, 2015
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:240875994
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Apr 15, 2015
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:240875994
Benign
Hetero
Gene:
KCNJ5
Variant:
c.*1216C>T
rsID: rs566376081
Ref Allele: C
Alt Allele: T
Freq: 0.2023%rare
CADD: 1.727
ClinVar Submissions (1)
A heritable form of hyperaldosteronism.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 11:128917947
Long QT syndrome (LQTS) is a cardiac electrophysiologic disorder, characterized by QT prolongation and T-wave abnormalities on the ECG that are associated with tachyarrhythmias, typically the ventricular tachycardia torsade de pointes (TdP). TdP is usually self-terminating, thus causing a syncopal event, the most common symptom in individuals with LQTS. Such cardiac events typically occur during exercise and emotional stress, less frequently during sleep, and usually without warning. In some instances, TdP degenerates to ventricular fibrillation and causes aborted cardiac arrest (if the individual is defibrillated) or sudden death. Approximately 50% of untreated individuals with a pathogenic variant in one of the genes associated with LQTS have symptoms, usually one to a few syncopal events. While cardiac events may occur from infancy through middle age, they are most common from the preteen years through the 20s. Some types of LQTS are associated with a phenotype extending beyond cardiac arrhythmia. In addition to the prolonged QT interval, associations include muscle weakness and facial dysmorphism in Andersen-Tawil syndrome (LQTS type 7), hand/foot, facial, and neurodevelopmental features in Timothy syndrome (LQTS type 8), and profound sensorineural hearing loss in Jervell and Lange-Nielson syndrome.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 11:128917947
Likely benign
Hetero
Gene:
SCN7A
Variant:
c.2048G>A
(p.Arg683Gln)
rsID: rs116825611
Ref Allele: C
Alt Allele: T
Freq: 0.2102%rare
CADD: 28.1
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Feb 07, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:166441505
Benign
Hetero
Gene:
TPK1
Variant:
c.663C>T
(p.Tyr221=)
rsID: rs113536847
Ref Allele: G
Alt Allele: A
Freq: 0.2134%rare
CADD: 10.03
ClinVar Submissions (2)
Episodic encephalopathy due to thiamine pyrophosphokinase deficiency is an autosomal recessive metabolic disorder due to an inborn error of thiamine metabolism. The phenotype is highly variable, but in general, affected individuals have onset in early childhood of acute encephalopathic episodes associated with increased serum and CSF lactate. These episodes result in progressive neurologic dysfunction manifest as gait disturbances, ataxia, dystonia, and spasticity, which in some cases may result in loss of ability to walk. Cognitive function is usually preserved, although mildly delayed development has been reported. These episodes are usually associated with infection and metabolic decompensation. Some patients may have recovery of some neurologic deficits (summary by Mayr et al., 2011). For a discussion of genetic heterogeneity of disorders due to thiamine metabolism dysfunction, see THMD1 (249270).
Last Evaluated: Jan 12, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 7:144453614
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jan 12, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 7:144453614
Benign
Hetero
Gene:
AKT2
Variant:
c.573+9C>T
rsID: rs3730258
Ref Allele: G
Alt Allele: A
Freq: 0.2214%rare
CADD: 0.39
ClinVar Submissions (2)
Type 2 diabetes is a disorder characterized by abnormally high blood sugar levels. In this form of diabetes, the body stops using and making insulin properly. Insulin is a hormone produced in the pancreas that helps regulate blood sugar levels. Specifically, insulin controls how much glucose (a type of sugar) is passed from the blood into cells, where it is used as an energy source. When blood sugar levels are high (such as after a meal), the pancreas releases insulin to move the excess glucose into cells, which reduces the amount of glucose in the blood.Most people who develop type 2 diabetes first have insulin resistance, a condition in which the body's cells use insulin less efficiently than normal. As insulin resistance develops, more and more insulin is needed to keep blood sugar levels in the normal range. To keep up with the increasing need, insulin-producing cells in the pancreas (called beta cells) make larger amounts of insulin. Over time, the beta cells become less able to respond to blood sugar changes, leading to an insulin shortage that prevents the body from reducing blood sugar levels effectively. Most people have some insulin resistance as they age, but inadequate exercise and excessive weight gain make it worse, greatly increasing the likelihood of developing type 2 diabetes.Type 2 diabetes can occur at any age, but it most commonly begins in middle age or later. Signs and symptoms develop slowly over years. They include frequent urination (polyuria), excessive thirst (polydipsia), fatigue, blurred vision, tingling or loss of feeling in the hands and feet (diabetic neuropathy), sores that do not heal well, and weight loss. If blood sugar levels are not controlled through medication or diet, type 2 diabetes can cause long-lasting (chronic) health problems including heart disease and stroke; nerve damage; and damage to the kidneys, eyes, and other parts of the body.
Last Evaluated: Dec 21, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 19:40241929
Last Evaluated: Dec 21, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 19:40241929
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Dec 21, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 19:40241929
Benign/Likely benign
Hetero
Gene:
GABRB1
Variant:
c.1263C>G
(p.His421Gln)
rsID: rs41311286
Ref Allele: C
Alt Allele: G
Freq: 0.2278%rare
CADD: 15.06
ClinVar Submissions (1)
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jun 02, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 4:47425856
Likely benign
Hetero
Gene:
ENPP1
Variant:
c.2335A>C
(p.Thr779Pro)
rsID: rs1805138
Ref Allele: A
Alt Allele: C
Freq: 0.2278%rare
CADD: 20.8
ClinVar Submissions (2)
Generalized arterial calcification of infancy (GACI) is characterized by infantile onset of widespread arterial calcification and/or narrowing of large- and medium-sized vessels resulting in cardiovascular findings (which can include heart failure, respiratory distress, edema, cyanosis, hypertension, and/or cardiomegaly). Additional findings can include extravascular calcifications (particularly periarticular), typical skin and retinal manifestations of pseudoxanthoma elasticum (PXE), hearing loss, and development of rickets after infancy. While mortality in infancy is high, survival into the second and third decade has been reported.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:131884954
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:131884954
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:131884954
Benign/Likely benign
Hetero
Gene:
PLOD3
Variant:
c.1935+105T>G
rsID: rs186082235
Ref Allele: A
Alt Allele: C
Freq: 0.2333%rare
CADD: 0.944
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 19, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:101207473
Likely benign
Hetero
Gene:
VCL
Variant:
c.3258+10A>T
rsID: rs71579379
Ref Allele: A
Alt Allele: T
Freq: 0.2469%rare
CADD: 3.119
ClinVar Submissions (4)
Last Evaluated: Dec 27, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 10:74114909
Last Evaluated: Dec 27, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 10:74114909
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Dec 27, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 10:74114909
Conflicting/Uncertain
Hetero
Gene:
EVC2
Variant:
c.3272+8G>A
rsID: rs201800139
Ref Allele: C
Alt Allele: T
Freq: 0.2588%rare
CADD: 0.072
ClinVar Submissions (6)
Ellis-van Creveld syndrome is an autosomal recessive skeletal dysplasia characterized by short limbs, short ribs, postaxial polydactyly, and dysplastic nails and teeth. Congenital cardiac defects, most commonly a defect of primary atrial septation producing a common atrium, occur in 60% of affected individuals (summary by Ruiz-Perez et al., 2000). The clinical features of the Ellis-van Creveld syndrome appear to be identical regardless of whether the disorder is caused by mutation in the EVC gene (604831) or in the EVC2 gene (607261) (Ruiz-Perez et al., 2003, Galdzicka et al., 2002).
Last Evaluated: Aug 24, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 4:5576232
Weyers acrofacial dysostosis is an autosomal dominant condition with dental anomalies, nail dystrophy, postaxial polydactyly, and mild short stature. Ellis-van Creveld syndrome is a similar disorder, with autosomal recessive inheritance and the additional features of disproportionate dwarfism, thoracic dysplasia, and congenital heart disease (summary by Howard et al., 1997).
Last Evaluated: Aug 24, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 4:5576232
Last Evaluated: Aug 24, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 4:5576232
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 24, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 4:5576232
Conflicting/Uncertain
Hetero
Gene:
ATL3
Variant:
c.1434A>G
(p.Gly478=)
rsID: rs189119869
Ref Allele: T
Alt Allele: C
Freq: 0.2668%rare
CADD: 4.452
ClinVar Submissions (1)
Hereditary sensory neuropathy type IF is an autosomal dominant sensory neuropathy affecting the lower limbs. Distal sensory impairment becomes apparent during the second or third decade of life, resulting in painless ulceration of the feet with poor healing, which can progress to osteomyelitis, bone destruction, and amputation. There is no autonomic involvement, spasticity, or cognitive impairment (summary by Kornak et al., 2014). For a discussion of genetic heterogeneity of HSN, see HSAN1A (162400).
Last Evaluated: Dec 17, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 11:63631145
Benign
Hetero
Gene:
SLC6A17
Variant:
c.2036A>G
(p.Lys679Arg)
rsID: rs41313405
Ref Allele: A
Alt Allele: G
Freq: 0.2732%rare
CADD: 21.7
ClinVar Submissions (1)
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Nov 07, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:110198296
Likely benign
Hetero
Gene:
CTSD
Variant:
c.912G>A
(p.Pro304=)
rsID: rs140238987
Ref Allele: C
Alt Allele: T
Freq: 0.2732%rare
CADD: 8.973
ClinVar Submissions (5)
Last Evaluated: Dec 28, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 5
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 11:1754054
The neuronal ceroid-lipofuscinoses (NCLs) are a group of inherited, neurodegenerative, lysosomal storage disorders characterized by progressive intellectual and motor deterioration, seizures, and early death. Visual loss is a feature of most forms. Clinical phenotypes have been characterized traditionally according to the age of onset and order of appearance of clinical features into infantile, late-infantile, juvenile, adult, and Northern epilepsy (also known as progressive epilepsy with mental retardation [EPMR]). There is however genetic and allelic heterogeneity; a proposed new nomenclature and classification system has been developed to take into account both the responsible gene and the age at disease onset; for example, CLN1 disease, infantile onset and CLN1 disease, juvenile onset are both caused by pathogenic variants in PPT1 but with differing age of onset. The most prevalent NCLs are CLN3 disease, classic juvenile and CLN2 disease, classic late infantile (although prevalence varies by ethnicity and country of family origin): CLN2 disease, classic late infantile. The first symptoms typically appear between age two and four years, usually starting with epilepsy, followed by regression of developmental milestones, myoclonic ataxia, and pyramidal signs. Visual impairment typically appears at age four to six years and rapidly progresses to light /dark awareness only. Life expectancy ranges from age six years to early teenage. CLN3 disease, classic juvenile. Onset is usually between ages four and ten years. Rapidly progressing visual loss resulting in severe visual impairment within one to two years is often the first clinical sign. Epilepsy with generalized tonic-clonic seizures and/or complex-partial seizures typically appears around age ten years. Life expectancy ranges from the late teens to the 30s. Other forms of NCL may present with behavior changes, epilepsy, visual impairment, or slowing of developmental progress and then loss of skills. The course may be extremely variable. Some genotype-phenotype information is available.
Last Evaluated: Dec 28, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 5
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 11:1754054
Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as EPILEPSY or "seizure disorder."
Last Evaluated: Dec 28, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 5
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 11:1754054
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Dec 28, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 5
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 11:1754054
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Dec 28, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 5
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 11:1754054
Conflicting/Uncertain
Hetero
Gene:
ACY1
Variant:
c.841C>T
(p.Arg281Cys)
rsID: rs121912698
Ref Allele: C
Alt Allele: T
Freq: 0.274%rare
CADD: 23.9
ClinVar Submissions (4)
Aminoacylase-1 deficiency (ACY1D) is a rare autosomal recessive inborn error of metabolism characterized by increased urinary excretion of specific N-actyl amino acids. Most patients show neurologic abnormalities such as intellectual disability, seizures, hypotonia, and motor delay (summary by Ferri et al., 2014).
Last Evaluated: Dec 03, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:51988821
OMIM Allelic Variant: 104620.0002
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Dec 03, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 3:51988821
OMIM Allelic Variant: 104620.0002
Clinically Significant Conflicting/Uncertain
Hetero
Gene:
NOTCH1
Variant:
c.3294C>T
(p.Ser1098=)
rsID: rs61751546
Ref Allele: G
Alt Allele: A
Freq: 0.2811%rare
CADD: 6.722
ClinVar Submissions (5)
Adams-Oliver syndrome (AOS) is characterized by aplasia cutis congenita (ACC) of the scalp and terminal transverse limb defects (TTLD). ACC lesions usually occur in the midline of the parietal or occipital regions, but can also occur on the abdomen or limbs. At birth, an ACC lesion may already have the appearance of a healed scar. ACC lesions less than 5 cm often involve only the skin and almost always heal over a period of months; larger lesions are more likely to involve the skull and possibly the dura, and are at greater risk for complications, which can include infection, hemorrhage, or thrombosis, and can result in death. The limb defects range from mild (unilateral or bilateral short distal phalanges) to severe (complete absence of all toes or fingers, feet or hands, or more, often resembling an amputation). The lower extremities are almost always more severely affected than the upper extremities. Additional major features frequently include cardiovascular malformations/dysfunction (23%), brain anomalies, and less frequently renal, liver, and eye anomalies.
Last Evaluated: Dec 16, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 9:136508263
Bicuspid, or bicommissural, aortic valve (BAV) describes an aortic valve with 2 rather than 3 leaflets (Cripe et al., 2004). In 1 to 2% of the population a bicuspid aortic valve is present. Bicuspid aortic valve is frequently an antecedent to aortic valve stenosis or insufficiency. In extreme cases the blood flow may be so restricted that the left ventricle fails to grow, resulting in hypoplastic left heart syndrome (241550) (Garg et al., 2005). The valve calcification often observed in bicuspid aortic valve is a result of inappropriate activation of osteoblast-specific gene expression. Mutations in the signaling and transcription regulator NOTCH1 cause a spectrum of developmental aortic valve anomalies and severe valve calcification in nonsyndromic autosomal dominant human pedigrees. Genetic Heterogeneity of Aortic Valve Disease Aortic valve disease-2 (AOVD2; 614823) is caused by mutation in the SMAD6 gene (602931) on chromosome 15q22. There is evidence for additional genetic heterogeneity (see MAPPING).
Last Evaluated: Dec 16, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 9:136508263
Last Evaluated: Dec 16, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 9:136508263
A heterogeneous group of disorders, some hereditary, others acquired, characterized by abnormal structure or function of one or more of the elements of connective tissue, i.e., collagen, elastin, or the mucopolysaccharides.
Last Evaluated: Dec 16, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 9:136508263
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Dec 16, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 9:136508263
Benign/Likely benign
Hetero
Gene:
TBC1D7
Variant:
c.413C>A
(p.Ala138Asp)
rsID: rs80189640
Ref Allele: G
Alt Allele: T
Freq: 0.2843%rare
CADD: 24.3
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Oct 31, 2015
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 6:13316677
Likely benign
Hetero
Gene:
SHANK3
Variant:
c.4960C>A
(p.Pro1654Thr)
rsID: rs749130556
Ref Allele: C
Alt Allele: A
Freq: 0.2843%rare
CADD: 17.26
ClinVar Submissions (2)
Last Evaluated: Jul 29, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 22:50731076
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 29, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 22:50731076
Conflicting/Uncertain
Hetero
Gene:
SCN1A
Variant:
c.*588A>G
rsID: rs539073575
Ref Allele: T
Alt Allele: C
Freq: 0.2891%rare
CADD: 13.96
ClinVar Submissions (1)
A brain disorder characterized by episodes of abnormally increased neuronal discharge resulting in transient episodes of sensory or motor neurological dysfunction, or psychic dysfunction. These episodes may or may not be associated with loss of consciousness or convulsions.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:165990657
Familial hemiplegic migraine (FHM) falls within the category of migraine with aura. In migraine with aura (including familial hemiplegic migraine) the neurologic symptoms of aura are unequivocally localizable to the cerebral cortex or brain stem and include visual disturbance (most common), sensory loss (e.g., numbness or paresthesias of the face or an extremity), and dysphasia (difficulty with speech); FHM must include motor involvement, i.e., hemiparesis (weakness of an extremity). Hemiparesis occurs with at least one other symptom during FHM aura. Neurologic deficits with FHM attacks can be prolonged for hours to days and may outlast the associated migrainous headache. FHM is often earlier in onset than typical migraine, frequently beginning in the first or second decade; the frequency of attacks tends to decrease with age. Approximately 40%-50% of families with FHM1 have cerebellar signs ranging from nystagmus to progressive, usually late-onset mild ataxia. Cerebral infarction and death have rarely been associated with hemiplegic migraine.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:165990657
Likely benign
Hetero
Gene:
TBX1
Variant:
c.444C>T
(p.Phe148=)
rsID: rs139776757
Ref Allele: C
Alt Allele: T
Freq: 0.2891%rare
CADD: 10.51
ClinVar Submissions (2)
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 22:19763274
Individuals with 22q11.2 deletion syndrome (22q11.2DS) have a range of findings including the following: Congenital heart disease (74% of individuals), particularly conotruncal malformations (tetralogy of Fallot, interrupted aortic arch, ventricular septal defect, and truncus arteriosus). Palatal abnormalities (69%), particularly velopharyngeal incompetence, submucosal cleft palate, bifid uvula, and cleft palate. Characteristic facial features (present in the majority of individuals of northern European heritage). Learning difficulties (70%-90%). An immune deficiency (regardless of the clinical presentation) (77%). Additional findings include the following: Hypocalcemia (50%). Significant feeding and swallowing problems; constipation with or without structural gastrointestinal anomalies (intestinal malrotation, imperforate anus, and Hirschsprung disease). Renal anomalies (31%). Hearing loss (both conductive and sensorineural). Laryngotracheoesophageal anomalies. Growth hormone deficiency. Autoimmune disorders. Seizures (idiopathic or associated with hypocalcemia). CNS anomalies including tethered cord. Skeletal abnormalities (scoliosis with or without vertebral anomalies, clubbed feet, polydactyly, and craniosynostosis). Ophthalmologic abnormalities (strabismus, posterior embryotoxon, tortuous retinal vessels, scleracornea, and anophthalmia). Enamel hypoplasia. Malignancies (rare). Developmental delay (in particular delays in emergence of language), intellectual disability, and learning differences (non-verbal learning disability where the verbal IQ is significantly greater than the performance IQ) are common. Autism or autistic spectrum disorder is found in approximately 20% of children and psychiatric illness (specifically schizophrenia) is present in 25% of adults; however, attention deficit disorder, anxiety, perseveration, and difficulty with social interactions are also common.
Last Evaluated: Jul 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 22:19763274
Benign/Likely benign
Hetero
Gene:
ATP1A2
Variant:
c.*932T>C
rsID: rs183455719
Ref Allele: T
Alt Allele: C
Freq: 0.2963%rare
CADD: 1.119
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 1:160142254
Familial hemiplegic migraine (FHM) falls within the category of migraine with aura. In migraine with aura (including familial hemiplegic migraine) the neurologic symptoms of aura are unequivocally localizable to the cerebral cortex or brain stem and include visual disturbance (most common), sensory loss (e.g., numbness or paresthesias of the face or an extremity), and dysphasia (difficulty with speech); FHM must include motor involvement, i.e., hemiparesis (weakness of an extremity). Hemiparesis occurs with at least one other symptom during FHM aura. Neurologic deficits with FHM attacks can be prolonged for hours to days and may outlast the associated migrainous headache. FHM is often earlier in onset than typical migraine, frequently beginning in the first or second decade; the frequency of attacks tends to decrease with age. Approximately 40%-50% of families with FHM1 have cerebellar signs ranging from nystagmus to progressive, usually late-onset mild ataxia. Cerebral infarction and death have rarely been associated with hemiplegic migraine.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 1:160142254
Conflicting/Uncertain
Hetero
Gene:
ATP1A2
Variant:
c.2943-15C>T
rsID: rs111510835
Ref Allele: C
Alt Allele: T
Freq: 0.305%rare
CADD: 10.62
ClinVar Submissions (2)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:160139878
Familial hemiplegic migraine (FHM) falls within the category of migraine with aura. In migraine with aura (including familial hemiplegic migraine) the neurologic symptoms of aura are unequivocally localizable to the cerebral cortex or brain stem and include visual disturbance (most common), sensory loss (e.g., numbness or paresthesias of the face or an extremity), and dysphasia (difficulty with speech); FHM must include motor involvement, i.e., hemiparesis (weakness of an extremity). Hemiparesis occurs with at least one other symptom during FHM aura. Neurologic deficits with FHM attacks can be prolonged for hours to days and may outlast the associated migrainous headache. FHM is often earlier in onset than typical migraine, frequently beginning in the first or second decade; the frequency of attacks tends to decrease with age. Approximately 40%-50% of families with FHM1 have cerebellar signs ranging from nystagmus to progressive, usually late-onset mild ataxia. Cerebral infarction and death have rarely been associated with hemiplegic migraine.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:160139878
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:160139878
Benign/Likely benign
Hetero
Gene:
MASP1
Variant:
c.1062G>A
(p.Thr354=)
rsID: rs116763673
Ref Allele: C
Alt Allele: T
Freq: 0.3106%rare
CADD: 0.996
ClinVar Submissions (1)
The term '3MC syndrome' encompasses 4 rare autosomal recessive disorders that were previously designated the Carnevale, Mingarelli, Malpuech, and Michels syndromes, respectively. The main features of these syndromes are facial dysmorphism that includes hypertelorism, blepharophimosis, blepharoptosis, and highly arched eyebrows, which are present in 70 to 95% of cases. Cleft lip and palate, postnatal growth deficiency, cognitive impairment, and hearing loss are also consistent findings, occurring in 40 to 68% of cases. Craniosynostosis, radioulnar synostosis, and genital and vesicorenal anomalies occur in 20 to 30% of cases. Rare features include anterior chamber defects, cardiac anomalies, caudal appendage, umbilical hernia (omphalocele), and diastasis recti (summary by Rooryck et al., 2011). Genetic Heterogeneity of 3MC Syndrome Also see 3MC syndrome-2 (3MC2; 265050), caused by mutation in the COLEC11 gene (612502), and 3MC syndrome-3 (3MC3; 248340), caused by mutation in the COLEC1 gene (607620).
Last Evaluated: Oct 31, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 3:187250279
Benign
Hetero
Gene:
RAB3GAP2
Variant:
c.*925C>T
rsID: rs185747953
Ref Allele: G
Alt Allele: A
Freq: 0.3289%rare
CADD: 11.21
ClinVar Submissions (1)
RAB18 deficiency is the molecular deficit underlying both Warburg micro syndrome (characterized by eye, nervous system, and endocrine abnormalities) and Martsolf syndrome (characterized by similar – but milder – findings). To date Warburg micro syndrome comprises >96% of reported individuals with genetically defined RAB18 deficiency. The hallmark ophthalmologic findings are bilateral congenital cataracts, usually accompanied by microphthalmia, microcornea (diameter <10), and small atonic pupils. Poor vision despite early cataract surgery likely results from progressive optic atrophy and cortical visual impairment. Individuals with Warburg micro syndrome have severe to profound intellectual disability (ID); those with Martsolf syndrome have mild to moderate ID. Some individuals with RAB18 deficiency also have epilepsy. In Warburg micro syndrome, a progressive ascending spastic paraplegia typically begins with spastic diplegia and contractures during the first year, followed by upper limb involvement leading to spastic quadriplegia after about age five years, often eventually causing breathing difficulties. In Martsolf syndrome infantile hypotonia is followed primarily by slowly progressive lower limb spasticity. Hypogonadism – when present – manifests in both syndromes, in males as micropenis and/or cryptorchidism and in females as hypoplastic labia minora, clitoral hypoplasia, and small introitus.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:220150326
Warburg Micro syndrome is a rare autosomal recessive syndrome characterized by microcephaly, microphthalmia, microcornea, congenital cataracts, optic atrophy, cortical dysplasia, in particular corpus callosum hypoplasia, severe mental retardation, spastic diplegia, and hypogonadism (summary by Morris-Rosendahl et al., 2010). Genetic Heterogeneity of Warburg Micro Syndrome Warburg Micro syndrome-2 (WARBM2; 614225) is caused by mutation in the RAB3GAP2 gene (609275) on chromosome 1q41. WARBM3 (614222) is caused by mutation in the RAB18 gene (602207) on chromosome 10p12. WARBM4 (615663) is caused by mutation in the TBC1D20 gene (611663) on chromosome 20p13. See also Martsolf syndrome (212720), a clinically overlapping but milder autosomal recessive disorder caused by autosomal recessive mutation in the RAB3GAP2 gene. Handley et al. (2013) provided an overview of the disease variants identified in the RAB3GAP1, RAB3GAP2, and RAB18 genes, noting that a total of 144 families with WARBM and 9 families with Martsolf syndrome had been studied. Mutations were identified in RAB3GAP1 in 41% of cases, in RAB3GAP2 in 7% of cases, and in RAB18 in 5% of cases. Although RAB18 had not been linked to RAB3 pathways, Handley et al. (2013) stated that mutations in all 3 genes cause an indistinguishable phenotype, making it likely that there is some functional overlap.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:220150326
Likely benign
Hetero
Gene:
NBAS
Variant:
c.3217C>T
(p.Arg1073Cys)
rsID: rs147322367
Ref Allele: G
Alt Allele: A
Freq: 0.3297%rare
CADD: 25.2
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Dec 16, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:15394267
Likely benign
Hetero
Gene:
FASN
Variant:
c.6374G>A
(p.Arg2125Gln)
rsID: rs145866788
Ref Allele: C
Alt Allele: T
Freq: 0.3297%rare
CADD: 0.02
ClinVar Submissions (1)
Last Evaluated: Nov 02, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 17:82081633
Benign
Hetero
Gene:
TCN2
Variant:
c.877C>T
(p.Leu293=)
rsID: rs45624233
Ref Allele: C
Alt Allele: T
Freq: 0.3393%rare
CADD: 16.09
ClinVar Submissions (2)
Transcobalamin II deficiency is an autosomal recessive disorder with onset in early infancy characterized by failure to thrive, megaloblastic anemia, and pancytopenia. Other features include methylmalonic aciduria, recurrent infections, and vomiting and diarrhea. Treatment with cobalamin results in clinical improvement, but the untreated disorder may result in mental retardation and neurologic abnormalities (summary by Haberle et al., 2009). Hall (1981) gave a clinically oriented review of congenital defects of vitamin B12 transport, and Frater-Schroder (1983) gave a genetically oriented review.
Last Evaluated: Nov 18, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 2
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 22:30615724
Conflicting/Uncertain
Hetero
Gene:
RAB3GAP1
Variant:
c.1006C>T
(p.Arg336Cys)
rsID: rs150478342
Ref Allele: C
Alt Allele: T
Freq: 0.3528%rare
CADD: 22.3
ClinVar Submissions (5)
Warburg Micro syndrome is a rare autosomal recessive syndrome characterized by microcephaly, microphthalmia, microcornea, congenital cataracts, optic atrophy, cortical dysplasia, in particular corpus callosum hypoplasia, severe mental retardation, spastic diplegia, and hypogonadism (summary by Morris-Rosendahl et al., 2010). Genetic Heterogeneity of Warburg Micro Syndrome Warburg Micro syndrome-2 (WARBM2; 614225) is caused by mutation in the RAB3GAP2 gene (609275) on chromosome 1q41. WARBM3 (614222) is caused by mutation in the RAB18 gene (602207) on chromosome 10p12. WARBM4 (615663) is caused by mutation in the TBC1D20 gene (611663) on chromosome 20p13. See also Martsolf syndrome (212720), a clinically overlapping but milder autosomal recessive disorder caused by autosomal recessive mutation in the RAB3GAP2 gene. Handley et al. (2013) provided an overview of the disease variants identified in the RAB3GAP1, RAB3GAP2, and RAB18 genes, noting that a total of 144 families with WARBM and 9 families with Martsolf syndrome had been studied. Mutations were identified in RAB3GAP1 in 41% of cases, in RAB3GAP2 in 7% of cases, and in RAB18 in 5% of cases. Although RAB18 had not been linked to RAB3 pathways, Handley et al. (2013) stated that mutations in all 3 genes cause an indistinguishable phenotype, making it likely that there is some functional overlap.
Last Evaluated: Jun 06, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 5
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:135130027
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jun 06, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 5
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:135130027
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 06, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 5
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:135130027
Conflicting/Uncertain
Hetero
Gene:
ZFHX3
Variant:
c.6156G>A
(p.Pro2052=)
rsID: rs148383343
Ref Allele: C
Alt Allele: T
Freq: 0.3552%rare
CADD: 0.247
ClinVar Submissions (1)
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Oct 31, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 16:72796526
Conflicting/Uncertain
Hetero
Gene:
BRCA2
Variant:
c.5199C>T
(p.Ser1733=)
rsID: rs28897734
Ref Allele: C
Alt Allele: T
Freq: 0.3632%rare
CADD: 0.015
ClinVar Submissions (27)
BRCA1- and BRCA2-associated hereditary breast and ovarian cancer syndrome (HBOC) is characterized by an increased risk for female and male breast cancer, ovarian cancer (includes fallopian tube and primary peritoneal cancers), and to a lesser extent other cancers such as prostate cancer, pancreatic cancer, and melanoma primarily in individuals with a BRCA2 pathogenic variant. The exact cancer risks differ slightly depending on whether HBOC is caused by a BRCA1 or BRCA2 pathogenic variant.
Last Evaluated: Jan 15, 2018
Review Status: reviewed by expert panel
Number of Submitters: 27
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 13:32339554
BRCA1- and BRCA2-associated hereditary breast and ovarian cancer syndrome (HBOC) is characterized by an increased risk for female and male breast cancer, ovarian cancer (includes fallopian tube and primary peritoneal cancers), and to a lesser extent other cancers such as prostate cancer, pancreatic cancer, and melanoma primarily in individuals with a BRCA2 pathogenic variant. The exact cancer risks differ slightly depending on whether HBOC is caused by a BRCA1 or BRCA2 pathogenic variant.
Last Evaluated: Jan 15, 2018
Review Status: reviewed by expert panel
Number of Submitters: 27
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 13:32339554
Fanconi anemia (FA) is characterized by physical abnormalities, bone marrow failure, and increased risk for malignancy. Physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. The incidence of acute myeloid leukemia is 13% by age 50 years. Solid tumors – particularly of the head and neck, skin, gastrointestinal tract, and genitourinary tract – are more common in individuals with FA.
Last Evaluated: Jan 15, 2018
Review Status: reviewed by expert panel
Number of Submitters: 27
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 13:32339554
BRCA1- and BRCA2-associated hereditary breast and ovarian cancer syndrome (HBOC) is characterized by an increased risk for female and male breast cancer, ovarian cancer (includes fallopian tube and primary peritoneal cancers), and to a lesser extent other cancers such as prostate cancer, pancreatic cancer, and melanoma primarily in individuals with a BRCA2 pathogenic variant. The exact cancer risks differ slightly depending on whether HBOC is caused by a BRCA1 or BRCA2 pathogenic variant.
Last Evaluated: Jan 15, 2018
Review Status: reviewed by expert panel
Number of Submitters: 27
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 13:32339554
The condition of a pattern of malignancies within a family, but not every individual's necessarily having the same neoplasm. Characteristically the tumor tends to occur at an earlier than average age, individuals may have more than one primary tumor, the tumors may be multicentric, usually more than 25 percent of the individuals in direct lineal descent from the proband are affected, and the cancer predisposition in these families behaves as an autosomal dominant trait with about 60 percent penetrance.
Last Evaluated: Jan 15, 2018
Review Status: reviewed by expert panel
Number of Submitters: 27
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 13:32339554
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jan 15, 2018
Review Status: reviewed by expert panel
Number of Submitters: 27
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 13:32339554
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jan 15, 2018
Review Status: reviewed by expert panel
Number of Submitters: 27
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 13:32339554
Expert Reviewed Benign
Hetero
Gene:
SLC12A6
Variant:
c.*2261G>A
rsID: rs181064062
Ref Allele: C
Alt Allele: T
Freq: 0.3639%rare
CADD: 0.378
ClinVar Submissions (1)
Hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC), a neurodevelopmental and neurodegenerative disorder, is characterized by severe progressive sensorimotor neuropathy with resulting hypotonia, areflexia, and amyotrophy and variable degrees of dysgenesis of the corpus callosum. Mild-to-severe intellectual disability and "psychotic episodes" during adolescence are observed. Sensory modalities are moderately to severely affected beginning in infancy. The average age of onset of walking is 3.8 years; the average age of loss of walking is 13.8 years; the average age of death is 33 years.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 15:34231620
Conflicting/Uncertain
Hetero
Gene:
ATXN2
Variant:
c.3000A>G
(p.Val1000=)
rsID: rs140262591
Ref Allele: T
Alt Allele: C
Freq: 0.3655%rare
CADD: 14.81
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 27, 2014
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 12:111470741
Conflicting/Uncertain
Hetero
Gene:
PARS2
Variant:
c.843C>T
(p.Asn281=)
rsID: rs145005088
Ref Allele: G
Alt Allele: A
Freq: 0.3878%rare
CADD: 6.544
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: May 26, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:54758319
Benign
Hetero
Gene:
GARS
Variant:
c.-177T>C
rsID: rs78980639
Ref Allele: T
Alt Allele: C
Freq: 0.407%rare
CADD: 8.904
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:30594745
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:30594745
An abnormality characterized by disruption of the normal functioning of peripheral axons.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:30594745
Likely benign
Hetero
Gene:
SLC25A12
Variant:
c.*965A>G
rsID: rs576061664
Ref Allele: T
Alt Allele: C
Freq: 0.4173%rare
CADD: 0.257
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 2:171784309
Conflicting/Uncertain
Hetero
Gene:
MYH3
Variant:
c.690C>G
(p.Ala230=)
rsID: rs147148934
Ref Allele: G
Alt Allele: C
Freq: 0.4213%rare
CADD: 18.06
ClinVar Submissions (2)
A non-progressive finding characterized by multiple joint contractures found throughout the body at birth.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 17:10648602
Freeman-Sheldon syndrome (FSS), or DA2A, is phenotypically similar to DA1. In addition to contractures of the hands and feet, FSS is characterized by oropharyngeal abnormalities, scoliosis, and a distinctive face that includes a very small oral orifice (often only a few millimeters in diameter at birth), puckered lips, and an H-shaped dimple of the chin; hence, FSS has been called 'whistling face syndrome.' The limb phenotypes of DA1 and FSS may be so similar that they can only be distinguished by the differences in facial morphology (summary by Bamshad et al., 2009). For a general phenotypic description and a discussion of genetic heterogeneity of distal arthrogryposis, see DA1 (108120).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 17:10648602
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 17:10648602
Likely benign
Hetero
Gene:
GLI3
Variant:
c.2179G>A
(p.Gly727Arg)
rsID: rs121917710
Ref Allele: C
Alt Allele: T
Freq: 0.4269%rare
CADD: 26.1
ClinVar Submissions (7)
Typical Greig cephalopolysyndactyly syndrome (GCPS) is characterized by preaxial polydactyly or mixed pre- and postaxial polydactyly, true widely spaced eyes, and macrocephaly. Individuals with mild GCPS may have subtle craniofacial findings. The mild end of the GCPS spectrum is a continuum with preaxial polysyndactyly type IV and crossed polydactyly (preaxial polydactyly of the feet and postaxial polydactyly of the hands plus syndactyly of fingers 3-4 and toes 1-3). Individuals with severe GCPS can have seizures, hydrocephalus, and intellectual disability.
Last Evaluated: May 03, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 7:41967848
OMIM Allelic Variant: 165240.0009
Typical Greig cephalopolysyndactyly syndrome (GCPS) is characterized by preaxial polydactyly or mixed pre- and postaxial polydactyly, true widely spaced eyes, and macrocephaly. Individuals with mild GCPS may have subtle craniofacial findings. The mild end of the GCPS spectrum is a continuum with preaxial polysyndactyly type IV and crossed polydactyly (preaxial polydactyly of the feet and postaxial polydactyly of the hands plus syndactyly of fingers 3-4 and toes 1-3). Individuals with severe GCPS can have seizures, hydrocephalus, and intellectual disability.
Last Evaluated: May 03, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 7:41967848
OMIM Allelic Variant: 165240.0009
Pallister-Hall syndrome (referred to as PHS in this entry) is characterized by a spectrum of anomalies ranging from polydactyly, asymptomatic bifid epiglottis, and hypothalamic hamartoma at the mild end to laryngotracheal cleft with neonatal lethality at the severe end. Individuals with mild PHS may be incorrectly diagnosed as having isolated postaxial polydactyly type A. Individuals with PHS can have pituitary insufficiency and may die as neonates from undiagnosed and untreated adrenal insufficiency.
Last Evaluated: May 03, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 7:41967848
OMIM Allelic Variant: 165240.0009
Pallister-Hall syndrome (referred to as PHS in this entry) is characterized by a spectrum of anomalies ranging from polydactyly, asymptomatic bifid epiglottis, and hypothalamic hamartoma at the mild end to laryngotracheal cleft with neonatal lethality at the severe end. Individuals with mild PHS may be incorrectly diagnosed as having isolated postaxial polydactyly type A. Individuals with PHS can have pituitary insufficiency and may die as neonates from undiagnosed and untreated adrenal insufficiency.
Last Evaluated: May 03, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 7:41967848
OMIM Allelic Variant: 165240.0009
A congenital abnormality characterized by more than 5 digits on a hand or foot.
Last Evaluated: May 03, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 7:41967848
OMIM Allelic Variant: 165240.0009
Polydactyly refers to the occurrence of supernumerary digits and is the most frequent of congenital hand and foot deformities. Based on the location of the extra digits, polydactyly can be classified into preaxial, involving the thumb or great toe; postaxial, affecting the fifth digit; and central, involving the 3 central digits. Postaxial polydactyly (PAP) is further subclassified into 2 types: in type A, a well-formed extra digit articulates with the fifth or a sixth metacarpal, whereas in type B, a rudimentary, poorly developed extra digit is present (summary by Umm-e-Kalsoom et al., 2012). Genetic Heterogeneity of Postaxial Polydactyly Other forms of postaxial polydactyly type A include PAPA2 (602085) on chromosome 13q21; PAPA3 (607324) on chromosome 19p13; PAPA4 (608562) on chromosome 7q22; PAPA5 (263450) on chromosome 13q13; PAPA6 (615226), caused by mutation in the ZNF141 gene (194648) on chromosome 4p16; PAPA7 (617642), caused by mutation in the IQCE gene (617631) on chromosome 7p22; and PAPA8 (618123), caused by mutation in the GLI1 gene (165220) on chromosome 12q13.
Last Evaluated: May 03, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 7:41967848
OMIM Allelic Variant: 165240.0009
Last Evaluated: May 03, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 7:41967848
OMIM Allelic Variant: 165240.0009
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: May 03, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 7:41967848
OMIM Allelic Variant: 165240.0009
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: May 03, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 7:41967848
OMIM Allelic Variant: 165240.0009
Low clinical importance, Uncertain pathogenic — Reported to cause postaxial polydactyly in a dominant manner. However it was only observed in one family, another linked variant in the region may have been causal. Data in the exome variant server shows 1 in 100 carry this variant, contracting the polydactyly effect -- if that hypothesis were true, this variant is common enough that it would account for a large fraction of cases (i.e. many other publications would exist confirming the hypothesis). Other variants in this gene cause Pallister-Hall syndrome, which causes many traits including polydactyly and hypothalamic hamartoma (a congenital brain malformation that can cause seizures).
Clinically Significant Conflicting/Uncertain
Hetero
Gene:
KIF1C
Variant:
c.1815G>A
(p.Leu605=)
rsID: rs78356534
Ref Allele: G
Alt Allele: A
Freq: 0.4277%rare
CADD: 13.73
ClinVar Submissions (2)
Autosomal recessive spastic ataxia is a neurologic disorder characterized by onset in the first 2 decades of cerebellar ataxia, dysarthria, and variable spasticity of the lower limbs. Cognition is not affected (summary by Dor et al., 2014). For a discussion of genetic heterogeneity of spastic ataxia, see SPAX1 (108600).
Last Evaluated: Oct 12, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:5020556
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Oct 12, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:5020556
Benign/Likely benign
Hetero
Gene:
PKD1
Variant:
c.8161+8G>A
rsID: rs199569003
Ref Allele: C
Alt Allele: T
Freq: 0.4285%rare
CADD: 0.13
ClinVar Submissions (3)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Sep 12, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 16:2104490
Benign/Likely benign
Hetero
Gene:
AMN
Variant:
c.829A>G
(p.Thr277Ala)
rsID: rs146499374
Ref Allele: A
Alt Allele: G
Freq: 0.43%rare
CADD: 5.48
ClinVar Submissions (1)
Type I MGCA is a rare autosomal recessive disorder of leucine catabolism. The metabolic landmark is urinary excretion of 3-methylglutaconic acid (3-MGA) and its derivatives 3-methylglutaric acid (3-MG) and 3-hydroxyisovaleric acid (3-HIVA). Two main presentations have been described: 1 with onset in childhood associated with the nonspecific finding of psychomotor retardation, and the other with onset in adulthood of a progressive neurodegenerative disorder characterized by ataxia, spasticity, and sometimes dementia; these patients develop white matter lesions in the brain. However, some asymptomatic pediatric patients have been identified by newborn screening and show no developmental abnormalities when reexamined later in childhood (summary by Wortmann et al., 2010). Genetic Heterogeneity and Classification of Methylglutaconic Aciduria Methylglutaconic aciduria is a clinically and genetically heterogeneous disorder. Type II MGCA (MGCA2), also known as Barth syndrome (BTHS; 302060), is caused by mutation in the tafazzin gene (TAZ; 300394) on chromosome Xq28. It is characterized by mitochondrial cardiomyopathy, short stature, skeletal myopathy, and recurrent infections; cognitive development is normal. Type III MGCA (MGCA3; 258501), caused by mutation in the OPA3 gene (606580) on chromosome 19q13, involves optic atrophy, movement disorder, and spastic paraplegia. In types II and III, the elevations of 3-methylglutaconate and 3-methylglutarate in urine are modest. Type IV MGCA (MGCA4; 250951) represents an unclassified group of patients who have severe psychomotor retardation and cerebellar dysgenesis. Type V MGCA (MGCA5; 610198), caused by mutation in the DNAJC19 gene (608977) on chromosome 3q26, is characterized by early-onset dilated cardiomyopathy with conduction defects, nonprogressive cerebellar ataxia, testicular dysgenesis, and growth failure in addition to 3-methylglutaconic aciduria (Chitayat et al., 1992; Davey et al., 2006). Type VI MGCA (MGCA6; 614739), caused by mutation in the SERAC1 gene (614725) on chromosome 6q25, includes deafness, encephalopathy, and a Leigh-like syndrome. Type VII MGCA (MGCA7; 616271), caused by mutation in the CLPB gene (616254) on chromosome 11q13, includes cataracts, neurologic involvement, and neutropenia. Type VIII MCGA (MGCA8; 617248) is caused by mutation in the HTRA2 gene (606441) on chromosome 2p13. Type IX MCGA (MGCA9; 617698) is caused by mutation in the TIMM50 gene (607381) on chromosome 19q13. Eriguchi et al. (2006) noted that type I MGCA is very rare, with only 13 patients reported in the literature as of 2003. Wortmann et al. (2013) proposed a pathomechanism-based classification for 'inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature.'
Last Evaluated: Jul 11, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 14:102929723
Benign
Hetero
Gene:
WDR62
Variant:
c.3946C>G
(p.Gln1316Glu)
rsID: rs35811023
Ref Allele: C
Alt Allele: G
Freq: 0.4372%rare
CADD: 6.341
ClinVar Submissions (7)
Last Evaluated: Feb 22, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 19:36103774
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Feb 22, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 19:36103774
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Feb 22, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 19:36103774
Conflicting/Uncertain
Hetero
Gene:
PDGFB
Variant:
c.635C>T
(p.Thr212Met)
rsID: rs114786489
Ref Allele: G
Alt Allele: A
Freq: 0.4372%rare
CADD: 18.6
ClinVar Submissions (2)
Dermatofibrosarcoma protuberans (DFSP) is an uncommon, locally aggressive, but rarely metastasizing tumor of the deep dermis and subcutaneous tissue. It typically presents during early or middle adult life and is most frequently located on the trunk and proximal extremities (Sandberg et al., 2003).
Last Evaluated: Jun 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 22:39225814
Benign
Hetero
Gene:
TRMU
Variant:
c.387A>G
(p.Ala129=)
rsID: rs144586525
Ref Allele: A
Alt Allele: G
Freq: 0.4412%rare
CADD: 0.131
ClinVar Submissions (3)
Acute infantile liver failure resulting from TRMU mutation is a transient disorder of hepatic function. In addition to elevated liver enzymes, jaundice, vomiting, coagulopathy, and hyperbilirubinemia, the presence of increased serum lactate is consistent with a defect in mitochondrial respiratory function. With supportive care, patients who survive the initial acute episode can recover and show normal development (Zeharia et al., 2009). See also transient infantile mitochondrial myopathy (MMIT; 500009), which is a similar disorder. A more severe, permanent disorder with some overlapping features is associated with mitochondrial DNA depletion (251880). See ILFS1 (615438) for information on syndromic infantile liver failure.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 22:46346453
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 22:46346453
Conflicting/Uncertain
Hetero
Gene:
TFAP2B
Variant:
c.*1981T>A
rsID: rs148498816
Ref Allele: T
Alt Allele: A
Freq: 0.4452%rare
CADD: 2.465
ClinVar Submissions (1)
Char syndrome is characterized by the triad of typical facial features, patent ductus arteriosus (PDA), and aplasia or hypoplasia of the middle phalanges of the fifth fingers. Typical facial features are flat midface, flat nasal bridge and broad flat nasal tip, wide-set eyes, downslanting palpebral fissures, mild ptosis, short philtrum resulting in a triangular mouth, and thickened (patulous) everted lips.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 6:50845373
Likely benign
Hetero
Gene:
MAP3K15;PDHA1
Variant:
c.3751C>G
(p.Gln1251Glu)
rsID: rs15943
Ref Allele: G
Alt Allele: C
Freq: 0.4571%rare
ClinVar Submissions (1)
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jul 12, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: X:19361522
Benign
Homo
Gene:
VIPAS39
Variant:
c.1242G>A
(p.Leu414=)
rsID: rs45447095
Ref Allele: C
Alt Allele: T
Freq: 0.4754%rare
CADD: 9.139
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Nov 10, 2014
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 14:77429705
Benign
Hetero
Gene:
ICOS
Variant:
c.*1094C>T
rsID: rs144036725
Ref Allele: C
Alt Allele: T
Freq: 0.4778%rare
CADD: 0.312
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 2:203960693
Conflicting/Uncertain
Hetero
Gene:
KCNC3
Variant:
c.2170+14C>T
rsID: rs189018316
Ref Allele: G
Alt Allele: A
Freq: 0.4778%rare
CADD: 4.362
ClinVar Submissions (2)
In the families described to date, the phenotype of spinocerebellar ataxia type 13 (SCA13) has ranged from slowly progressive childhood-onset cerebellar gait ataxia associated with cerebellar dysarthria and often accompanied by mild intellectual disability and occasional seizures to adult-onset progressive ataxia. Life span is not shortened and many persons live beyond age 70 years, but assistance with gait may be required as the disease progresses.
Last Evaluated: Sep 21, 2015
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 19:50320579
Benign/Likely benign
Hetero
Gene:
MYH3
Variant:
c.4356+11C>T
rsID: rs150348272
Ref Allele: G
Alt Allele: A
Freq: 0.5009%rare
CADD: 0.004
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 17:10634829
Likely benign
Hetero
Gene:
EFHC1
Variant:
c.-162C>T
rsID: rs41273738
Ref Allele: C
Alt Allele: T
Freq: 0.5057%rare
CADD: 10.78
ClinVar Submissions (1)
Juvenile myoclonic epilepsy is a subtype of idiopathic generalized epilepsy (EIG; see 600669) affecting up to 26% of all individuals with EIG. Individuals with JME have afebrile seizures only, with onset in adolescence of myoclonic jerks. Myoclonic jerks occur usually in the morning (Janz and Durner, 1997). Genetic Heterogeneity of Juvenile Myoclonic Seizures Susceptibility to EJM can be conferred by variation in several other genes: EJM5 (611136), by variation in the GABRA1 gene (137160) on 5q34; EJM6 (see 607682), by variation in the CACNB4 gene (601949) on 2q23; EJM7 (see 613060), by variation in the GABRD gene (137163) on 1p36; EJM8 (see 607628), by variation in the CLCN2 gene (600570) on 3q27; and EJM10 (617924), by variation in the ICK gene (612325) on chromosome 6p12. In addition, EJM loci have been identified by linkage analysis: EJM2 (see 604827) on 15q14, EJM3 (608816) on 6p21, EJM4 (611364) on 5q12-q14, and EJM9 (614280) on 2q33-q36.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 6:52420249
Conflicting/Uncertain
Hetero
Gene:
ARID1B
Variant:
c.736G>A
(p.Gly246Ser)
rsID: rs375160616
Ref Allele: G
Alt Allele: A
Freq: 0.5105%rare
CADD: 22.5
ClinVar Submissions (3)
Last Evaluated: Feb 06, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 6:156778665
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Feb 06, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 6:156778665
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Feb 06, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 6:156778665
Benign
Hetero
Gene:
DOK7
Variant:
c.134C>T
(p.Ser45Leu)
rsID: rs62272670
Ref Allele: C
Alt Allele: T
Freq: 0.5169%rare
CADD: 11.35
ClinVar Submissions (6)
Congenital myasthenic syndromes (designated as CMS throughout this entry) are characterized by fatigable weakness of skeletal muscle (e.g., ocular, bulbar, limb muscles) with onset at or shortly after birth or in early childhood; rarely, symptoms may not manifest until later in childhood. Cardiac and smooth muscle are usually not involved. Severity and course of disease are highly variable, ranging from minor symptoms to progressive disabling weakness. In some subtypes of CMS, myasthenic symptoms may be mild, but sudden severe exacerbations of weakness or even sudden episodes of respiratory insufficiency may be precipitated by fever, infections, or excitement. Major findings of the neonatal-onset subtype include: respiratory insufficiency with sudden apnea and cyanosis; feeding difficulties; poor suck and cry; choking spells; eyelid ptosis; and facial, bulbar, and generalized weakness. Arthrogryposis multiplex congenita may also be present. Stridor in infancy may be an important clue to CMS. Later childhood-onset subtypes show abnormal muscle fatigability with difficulty in activities such as running or climbing stairs; motor milestones may be delayed; fluctuating eyelid ptosis and fixed or fluctuating extraocular muscle weakness are common presentations.
Last Evaluated: May 02, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 4:3473439
The fetal akinesia deformation sequence (FADS) refers to a clinically and genetically heterogeneous constellation of features including fetal akinesia, intrauterine growth retardation, arthrogryposis, and developmental anomalies, including lung hypoplasia, cleft palate, and cryptorchidism (Vogt et al., 2009). It shows phenotypic overlap with the lethal form of multiple pterygium syndrome (see 253290).
Last Evaluated: May 02, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 4:3473439
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: May 02, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 4:3473439
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: May 02, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 4:3473439
High clinical importance, Uncertain pathogenic — This variant was seen as a compound heterozygote (with either P376PfsX30 or P469H) in two individuals with congenital myasthenic syndromes (out of a screen of 200). Other mutations in this gene are associated with the syndrome, but there are insufficient controls to establish this variant in particular as significant.
Conflicting/Uncertain
Hetero
Gene:
POMT1
Variant:
c.*338T>G
rsID: rs193003183
Ref Allele: T
Alt Allele: G
Freq: 0.5272%rare
CADD: 2.173
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 9:131523444
Conflicting/Uncertain
Hetero
Gene:
SLC26A2
Variant:
c.*330G>T
rsID: rs191884433
Ref Allele: G
Alt Allele: T
Freq: 0.5288%rare
CADD: 0.046
ClinVar Submissions (1)
A rare group of disorders characterized by defective development of bones and cartilage.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 5:149982143
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 5:149982143
Diastrophic dysplasia (DTD) is characterized by limb shortening, normal-sized skull, hitchhiker thumbs, spinal deformities (scoliosis, exaggerated lumbar lordosis, cervical kyphosis), and contractures of the large joints with deformities and early-onset osteoarthritis. Other typical findings are ulnar deviation of the fingers, gap between the first and second toes, and clubfoot. On occasion the disease can be lethal at birth, but most affected individuals survive the neonatal period and develop physical limitations with normal intelligence.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 5:149982143
Recessive multiple epiphyseal dysplasia (EDM4/rMED) is characterized by joint pain (usually in the hips or knees); malformations of hands, feet, and knees; and scoliosis. Approximately 50% of affected individuals have an abnormal finding at birth, e.g., clubfoot, clinodactyly, or (rarely) cystic ear swelling. Onset of articular pain is variable but usually occurs in late childhood. Stature is usually within the normal range prior to puberty; in adulthood, stature is only slightly diminished and ranges from 150 to 180 cm. Functional disability is mild.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 5:149982143
A general term describing features characterized by abnormal development of bones and connective tissues. [HPO:probinson]
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 5:149982143
Conflicting/Uncertain
Hetero
Gene:
PIGW
Variant:
c.705C>G
(p.His235Gln)
rsID: rs61755368
Ref Allele: C
Alt Allele: G
Freq: 0.5312%rare
CADD: 23.5
ClinVar Submissions (1)
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Nov 30, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 17:36537806
Likely benign
Hetero
Gene:
CHD7
Variant:
c.*1502G>A
rsID: rs181017286
Ref Allele: G
Alt Allele: A
Freq: 0.532%rare
CADD: 0.071
ClinVar Submissions (1)
CHARGE is a mnemonic for coloboma, heart defects, choanal atresia, retarded growth and development, genital abnormalities, and ear anomalies. CHARGE syndrome is characterized by the following: Unilateral or bilateral coloboma of the iris, retina-choroid, and/or disc with or without microphthalmos (80%-90% of individuals). Unilateral or bilateral choanal atresia or stenosis (50%-60%). Cranial nerve dysfunction resulting in hyposmia or anosmia, unilateral or bilateral facial palsy (40%), impaired hearing, and/or swallowing problems (70%-90%). Abnormal outer ears, ossicular malformations, Mondini defect of the cochlea and absent or hypoplastic semicircular canals (>90%). Cryptorchidism in males and hypogonadotropic hypogonadism in both males and females. Developmental delay. Cardiovascular malformations (75%-85%). Growth deficiency (70%-80%). Orofacial clefts (15%-20%). Tracheoesophageal fistula (15%-20%). Neonates with CHARGE syndrome often have multiple life-threatening medical conditions. Feeding difficulties are a major cause of morbidity in all age groups.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 8:60867435
Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is characterized by inappropriately low serum concentrations of the gonadotropins LH (luteinizing hormone) and FSH (follicle-stimulating hormone) in the presence of low circulating concentrations of sex steroids. IGD is associated with a normal sense of smell (normosmic IGD) in approximately 40% of affected individuals and an impaired sense of smell (Kallmann syndrome) in approximately 60%. IGD can first become apparent in infancy, adolescence, or adulthood. Infant boys with congenital IGD often have micropenis and cryptorchidism. Adolescents and adults with IGD have clinical evidence of hypogonadism and incomplete sexual maturation on physical examination. Adult males with IGD tend to have prepubertal testicular volume (i.e., <4 mL), absence of secondary sexual features (e.g., facial and axillary hair growth, deepening of the voice), decreased muscle mass, diminished libido, erectile dysfunction, and infertility. Adult females have little or no breast development and primary amenorrhea. Although skeletal maturation is delayed, the rate of linear growth is usually normal except for the absence of a distinct pubertal growth spurt.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 8:60867435
Likely benign
Hetero
Gene:
TRIOBP
Variant:
c.391G>A
(p.Gly131Ser)
rsID: rs144634857
Ref Allele: G
Alt Allele: A
Freq: 0.536%rare
CADD: 0.462
ClinVar Submissions (5)
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jul 31, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 22:37713346
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 31, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 22:37713346
Benign/Likely benign
Hetero
Gene:
FGFR2
Variant:
c.294G>A
(p.Thr98=)
rsID: rs1047101
Ref Allele: C
Alt Allele: T
Freq: 0.5447%rare
CADD: 8.174
ClinVar Submissions (4)
The eight disorders comprising the FGFR-related craniosynostosis spectrum are Pfeiffer syndrome, Apert syndrome, Crouzon syndrome, Beare-Stevenson syndrome, FGFR2-related isolated coronal synostosis, Jackson-Weiss syndrome, Crouzon syndrome with acanthosis nigricans (AN), and Muenke syndrome (isolated coronal synostosis caused by the p.Pro250Arg pathogenic variant in FGFR3). Muenke syndrome and FGFR2-related isolated coronal synostosis are characterized only by uni- or bicoronal craniosynostosis; the remainder are characterized by bicoronal craniosynostosis or cloverleaf skull, distinctive facial features, and variable hand and foot findings.
Last Evaluated: Nov 06, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 10:121565520
Last Evaluated: Nov 06, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 10:121565520
The eight disorders comprising the FGFR-related craniosynostosis spectrum are Pfeiffer syndrome, Apert syndrome, Crouzon syndrome, Beare-Stevenson syndrome, FGFR2-related isolated coronal synostosis, Jackson-Weiss syndrome, Crouzon syndrome with acanthosis nigricans (AN), and Muenke syndrome (isolated coronal synostosis caused by the p.Pro250Arg pathogenic variant in FGFR3). Muenke syndrome and FGFR2-related isolated coronal synostosis are characterized only by uni- or bicoronal craniosynostosis; the remainder are characterized by bicoronal craniosynostosis or cloverleaf skull, distinctive facial features, and variable hand and foot findings.
Last Evaluated: Nov 06, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 10:121565520
The eight disorders comprising the FGFR-related craniosynostosis spectrum are Pfeiffer syndrome, Apert syndrome, Crouzon syndrome, Beare-Stevenson syndrome, FGFR2-related isolated coronal synostosis, Jackson-Weiss syndrome, Crouzon syndrome with acanthosis nigricans (AN), and Muenke syndrome (isolated coronal synostosis caused by the p.Pro250Arg pathogenic variant in FGFR3). Muenke syndrome and FGFR2-related isolated coronal synostosis are characterized only by uni- or bicoronal craniosynostosis; the remainder are characterized by bicoronal craniosynostosis or cloverleaf skull, distinctive facial features, and variable hand and foot findings.
Last Evaluated: Nov 06, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 10:121565520
Last Evaluated: Nov 06, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 10:121565520
The eight disorders comprising the FGFR-related craniosynostosis spectrum are Pfeiffer syndrome, Apert syndrome, Crouzon syndrome, Beare-Stevenson syndrome, FGFR2-related isolated coronal synostosis, Jackson-Weiss syndrome, Crouzon syndrome with acanthosis nigricans (AN), and Muenke syndrome (isolated coronal synostosis caused by the p.Pro250Arg pathogenic variant in FGFR3). Muenke syndrome and FGFR2-related isolated coronal synostosis are characterized only by uni- or bicoronal craniosynostosis; the remainder are characterized by bicoronal craniosynostosis or cloverleaf skull, distinctive facial features, and variable hand and foot findings.
Last Evaluated: Nov 06, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 10:121565520
The eight disorders comprising the FGFR-related craniosynostosis spectrum are Pfeiffer syndrome, Apert syndrome, Crouzon syndrome, Beare-Stevenson syndrome, FGFR2-related isolated coronal synostosis, Jackson-Weiss syndrome, Crouzon syndrome with acanthosis nigricans (AN), and Muenke syndrome (isolated coronal synostosis caused by the p.Pro250Arg pathogenic variant in FGFR3). Muenke syndrome and FGFR2-related isolated coronal synostosis are characterized only by uni- or bicoronal craniosynostosis; the remainder are characterized by bicoronal craniosynostosis or cloverleaf skull, distinctive facial features, and variable hand and foot findings.
Last Evaluated: Nov 06, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 10:121565520
Lacrimoauriculodentodigital syndrome is a multiple congenital anomaly disorder mainly affecting lacrimal glands and ducts, salivary glands and ducts, ears, teeth, and distal limb segments (summary by Rohmann et al., 2006).
Last Evaluated: Nov 06, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 10:121565520
Last Evaluated: Nov 06, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 10:121565520
Classic Saethre-Chotzen syndrome (SCS) is characterized by coronal synostosis (unilateral or bilateral), facial asymmetry (particularly in individuals with unicoronal synostosis), strabismus, ptosis, and characteristic appearance of the ear (small pinna with a prominent superior and/or inferior crus). Syndactyly of digits two and three of the hand is variably present. Cognitive development is usually normal, although those with a large genomic deletion are at an increased risk for intellectual challenges. Less common manifestations of SCS include other skeletal findings (parietal foramina, vertebral segmentation defects, radioulnar synostosis, maxillary hypoplasia, ocular hypertelorism, hallux valgus, duplicated or curved distal hallux), hypertelorism, palatal anomalies, obstructive sleep apnea, increased intracranial pressure, short stature, and congenital heart malformations.
Last Evaluated: Nov 06, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 10:121565520
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Nov 06, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 10:121565520
Benign/Likely benign
Hetero
Gene:
LYST
Variant:
c.10941-7C>A
rsID: rs72761794
Ref Allele: G
Alt Allele: T
Freq: 0.563%rare
CADD: 10.94
ClinVar Submissions (5)
Chediak-Higashi syndrome (CHS) is characterized by partial oculocutaneous albinism, immunodeficiency, and a mild bleeding tendency. Approximately 85% of affected individuals develop the accelerated phase, or hemophagocytic lymphohistiocytosis, a life-threatening, hyperinflammatory condition. All affected individuals including adolescents and adults with atypical CHS and children with classic CHS who have successfully undergone allogenic hematopoietic stem cell transplantation (HSCT) develop neurologic findings during early adulthood.
Last Evaluated: Dec 22, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 5
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 1:235677195
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Dec 22, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 5
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 1:235677195
Conflicting/Uncertain
Hetero
Gene:
MLH3
Variant:
c.*1376C>T
rsID: rs117160510
Ref Allele: G
Alt Allele: A
Freq: 0.5726%rare
CADD: 0.848
ClinVar Submissions (1)
Lynch syndrome is characterized by an increased risk for colorectal cancer (CRC) and cancers of the endometrium, stomach, ovary, small bowel, hepatobiliary tract, urinary tract, brain, and skin. In individuals with Lynch syndrome the following lifetime risks for cancer are seen: CRC: 52%-82% (mean age at diagnosis 44-61 years). Endometrial cancer in females: 25%-60% (mean age at diagnosis 48-62 years). Gastric cancer: 6%-13% (mean age at diagnosis 56 years). Ovarian cancer: 4%-12% (mean age at diagnosis 42.5 years; ~30% are diagnosed < age 40 years). The risk for other Lynch syndrome-related cancers is lower, though substantially increased over general population rates.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 14:75015706
Conflicting/Uncertain
Hetero
Gene:
FANCF
Variant:
c.557C>T
(p.Ala186Val)
rsID: rs113910234
Ref Allele: G
Alt Allele: A
Freq: 0.5814%rare
CADD: 9.125
ClinVar Submissions (6)
Fanconi anemia (FA) is characterized by physical abnormalities, bone marrow failure, and increased risk for malignancy. Physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. The incidence of acute myeloid leukemia is 13% by age 50 years. Solid tumors – particularly of the head and neck, skin, gastrointestinal tract, and genitourinary tract – are more common in individuals with FA.
Last Evaluated: Jan 02, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 11:22625254
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jan 02, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 11:22625254
Conflicting/Uncertain
Hetero
Gene:
SCN10A
Variant:
c.45C>T
(p.Arg15=)
rsID: rs34314583
Ref Allele: G
Alt Allele: A
Freq: 0.5837%rare
CADD: 3.22
ClinVar Submissions (2)
Brugada syndrome is characterized by cardiac conduction abnormalities (ST-segment abnormalities in leads V1-V3 on ECG and a high risk for ventricular arrhythmias) that can result in sudden death. Brugada syndrome presents primarily during adulthood although age at diagnosis may range from infancy to late adulthood. The mean age of sudden death is approximately 40 years. Clinical presentations may also include sudden infant death syndrome (SIDS; death of a child during the first year of life without an identifiable cause) and the sudden unexpected nocturnal death syndrome (SUNDS), a typical presentation in individuals from Southeast Asia. Other conduction defects can include first-degree AV block, intraventricular conduction delay, right bundle branch block, and sick sinus syndrome.
Last Evaluated: Dec 27, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 3:38793966
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Dec 27, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 3:38793966
Benign
Hetero
Gene:
APC
Variant:
c.1312+27G>A
rsID: rs74975092
Ref Allele: G
Alt Allele: A
Freq: 0.6116%rare
CADD: 8.725
ClinVar Submissions (2)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 15, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 5:112819371
Benign
Hetero
Gene:
TRMU
Variant:
c.-281G>A
rsID: rs148373924
Ref Allele: G
Alt Allele: A
Freq: 0.6299%rare
CADD: 0.078
ClinVar Submissions (1)
Acute infantile liver failure resulting from TRMU mutation is a transient disorder of hepatic function. In addition to elevated liver enzymes, jaundice, vomiting, coagulopathy, and hyperbilirubinemia, the presence of increased serum lactate is consistent with a defect in mitochondrial respiratory function. With supportive care, patients who survive the initial acute episode can recover and show normal development (Zeharia et al., 2009). See also transient infantile mitochondrial myopathy (MMIT; 500009), which is a similar disorder. A more severe, permanent disorder with some overlapping features is associated with mitochondrial DNA depletion (251880). See ILFS1 (615438) for information on syndromic infantile liver failure.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 22:46335484
Conflicting/Uncertain
Hetero
Gene:
D2HGDH
Variant:
c.1063G>A
(p.Gly355Ser)
rsID: rs139321130
Ref Allele: G
Alt Allele: A
Freq: 0.6562%rare
CADD: 12.96
ClinVar Submissions (3)
An increased concentration of 2-hydroxyglutaric acid in the urine.
Last Evaluated: Mar 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:241751311
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Mar 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:241751311
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:241751311
Likely benign
Hetero
Gene:
PLAU
Variant:
c.43G>T
(p.Val15Leu)
rsID: rs2227580
Ref Allele: G
Alt Allele: T
Freq: 0.6618%rare
CADD: 17.36
ClinVar Submissions (1)
Quebec platelet disorder is an autosomal dominant bleeding disorder due to a gain-of-function defect in fibrinolysis. Although affected individuals do not exhibit systemic fibrinolysis, they show delayed onset bleeding after challenge, such as surgery. The hallmark of the disorder is markedly increased PLAU levels within platelets, which causes intraplatelet plasmin generation and secondary degradation of alpha-granule proteins. The disorder shows a favorable therapeutic response to fibrinolytic inhibitors (summary by Diamandis et al., 2009).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 10:73911598
Benign
Hetero
Gene:
PMS2
Variant:
c.1688G>T
(p.Arg563Leu)
rsID: rs63750668
Ref Allele: C
Alt Allele: A
Freq: 0.665%rare
CADD: 4.787
ClinVar Submissions (20)
The condition of a pattern of malignancies within a family, but not every individual's necessarily having the same neoplasm. Characteristically the tumor tends to occur at an earlier than average age, individuals may have more than one primary tumor, the tumors may be multicentric, usually more than 25 percent of the individuals in direct lineal descent from the proband are affected, and the cancer predisposition in these families behaves as an autosomal dominant trait with about 60 percent penetrance.
Last Evaluated: Jan 15, 2018
Review Status: reviewed by expert panel
Number of Submitters: 20
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:5987077
A group of autosomal-dominant inherited diseases in which COLON CANCER arises in discrete adenomas. Unlike FAMILIAL POLYPOSIS COLI with hundreds of polyps, hereditary nonpolyposis colorectal neoplasms occur much later, in the fourth and fifth decades. HNPCC has been associated with germline mutations in mismatch repair (MMR) genes. It has been subdivided into Lynch syndrome I or site-specific colonic cancer, and LYNCH SYNDROME II which includes extracolonic cancer.
Last Evaluated: Jan 15, 2018
Review Status: reviewed by expert panel
Number of Submitters: 20
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:5987077
Lynch syndrome, often called hereditary nonpolyposis colorectal cancer (HNPCC), is an inherited disorder that increases the risk of many types of cancer, particularly cancers of the colon (large intestine) and rectum, which are collectively referred to as colorectal cancer. People with Lynch syndrome also have an increased risk of cancers of the stomach, small intestine, liver, gallbladder ducts, upper urinary tract, brain, and skin. Additionally, women with this disorder have a high risk of cancer of the ovaries and lining of the uterus (the endometrium). People with Lynch syndrome may occasionally have noncancerous (benign) growths (polyps) in the colon, called colon polyps. In individuals with this disorder, colon polyps occur earlier but not in greater numbers than they do in the general population.
Last Evaluated: Jan 15, 2018
Review Status: reviewed by expert panel
Number of Submitters: 20
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:5987077
Lynch syndrome is characterized by an increased risk for colorectal cancer (CRC) and cancers of the endometrium, stomach, ovary, small bowel, hepatobiliary tract, urinary tract, brain, and skin. In individuals with Lynch syndrome the following lifetime risks for cancer are seen: CRC: 52%-82% (mean age at diagnosis 44-61 years). Endometrial cancer in females: 25%-60% (mean age at diagnosis 48-62 years). Gastric cancer: 6%-13% (mean age at diagnosis 56 years). Ovarian cancer: 4%-12% (mean age at diagnosis 42.5 years; ~30% are diagnosed < age 40 years). The risk for other Lynch syndrome-related cancers is lower, though substantially increased over general population rates.
Last Evaluated: Jan 15, 2018
Review Status: reviewed by expert panel
Number of Submitters: 20
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:5987077
Lynch syndrome is characterized by an increased risk for colorectal cancer (CRC) and cancers of the endometrium, stomach, ovary, small bowel, hepatobiliary tract, urinary tract, brain, and skin. In individuals with Lynch syndrome the following lifetime risks for cancer are seen: CRC: 52%-82% (mean age at diagnosis 44-61 years). Endometrial cancer in females: 25%-60% (mean age at diagnosis 48-62 years). Gastric cancer: 6%-13% (mean age at diagnosis 56 years). Ovarian cancer: 4%-12% (mean age at diagnosis 42.5 years; ~30% are diagnosed < age 40 years). The risk for other Lynch syndrome-related cancers is lower, though substantially increased over general population rates.
Last Evaluated: Jan 15, 2018
Review Status: reviewed by expert panel
Number of Submitters: 20
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:5987077
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jan 15, 2018
Review Status: reviewed by expert panel
Number of Submitters: 20
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:5987077
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jan 15, 2018
Review Status: reviewed by expert panel
Number of Submitters: 20
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:5987077
Expert Reviewed Likely benign
Hetero
Gene:
CACNA1S
Variant:
c.1817G>A
(p.Ser606Asn)
rsID: rs142356235
Ref Allele: C
Alt Allele: T
Freq: 0.6825%rare
CADD: 22.7
ClinVar Submissions (5)
Hypokalemic periodic paralysis (hypoPP) is a condition in which affected individuals may experience paralytic episodes with concomitant hypokalemia (serum potassium <3.5 mmol/L). The paralytic attacks are characterized by decreased muscle tone (flaccidity) more marked proximally than distally with normal to decreased deep tendon reflexes. The episodes develop over minutes to hours and last several minutes to several days with spontaneous recovery. Some individuals have only one episode in a lifetime; more commonly, crises occur repeatedly: daily, weekly, monthly, or less often. The major triggering factors are cessation of effort following strenuous exercise and carbohydrate-rich evening meals. Additional triggers can include cold, stress/excitement/fear, salt intake, prolonged immobility, use of glucosteroids or alcohol, and anesthetic procedures. The age of onset of the first attack ranges from two to 30 years; the duration of paralytic episodes ranges from one to 72 hours with an average of nearly 24 hours. Long-lasting interictal muscle weakness may occur in some affected individuals and in some stages of the disease and in myopathic muscle changes. A myopathy may occur independent of paralytic symptoms and may be the sole manifestation of hypoPP.
Last Evaluated: May 30, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:201076930
Hypokalemic periodic paralysis (hypoPP) is a condition in which affected individuals may experience paralytic episodes with concomitant hypokalemia (serum potassium <3.5 mmol/L). The paralytic attacks are characterized by decreased muscle tone (flaccidity) more marked proximally than distally with normal to decreased deep tendon reflexes. The episodes develop over minutes to hours and last several minutes to several days with spontaneous recovery. Some individuals have only one episode in a lifetime; more commonly, crises occur repeatedly: daily, weekly, monthly, or less often. The major triggering factors are cessation of effort following strenuous exercise and carbohydrate-rich evening meals. Additional triggers can include cold, stress/excitement/fear, salt intake, prolonged immobility, use of glucosteroids or alcohol, and anesthetic procedures. The age of onset of the first attack ranges from two to 30 years; the duration of paralytic episodes ranges from one to 72 hours with an average of nearly 24 hours. Long-lasting interictal muscle weakness may occur in some affected individuals and in some stages of the disease and in myopathic muscle changes. A myopathy may occur independent of paralytic symptoms and may be the sole manifestation of hypoPP.
Last Evaluated: May 30, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:201076930
Malignant hyperthermia susceptibility (MHS) is a pharmacogenetic disorder of skeletal muscle calcium regulation associated with uncontrolled skeletal muscle hypermetabolism. Manifestations of malignant hyperthermia (MH) are precipitated by certain volatile anesthetics (i.e., halothane, isoflurane, sevoflurane, desflurane, enflurane), either alone or in conjunction with a depolarizing muscle relaxant (specifically, succinylcholine). The triggering substances release calcium stores from the sarcoplasmic reticulum and may promote entry of calcium from the myoplasm, causing contracture of skeletal muscles, glycogenolysis, and increased cellular metabolism, resulting in production of heat and excess lactate. Affected individuals experience: acidosis, hypercapnia, tachycardia, hyperthermia, muscle rigidity, compartment syndrome, rhabdomyolysis with subsequent increase in serum creatine kinase (CK) concentration, hyperkalemia with a risk for cardiac arrhythmia or even arrest, and myoglobinuria with a risk for renal failure. In nearly all cases, the first manifestations of MH (tachycardia and tachypnea) occur in the operating room; however, MH may also occur in the early postoperative period. There is mounting evidence that some affected individuals will also develop MH with exercise and/or on exposure to hot environments. Without proper and prompt treatment with dantrolene sodium, mortality is extremely high.
Last Evaluated: May 30, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:201076930
Malignant hyperthermia susceptibility (MHS) is a pharmacogenetic disorder of skeletal muscle calcium regulation associated with uncontrolled skeletal muscle hypermetabolism. Manifestations of malignant hyperthermia (MH) are precipitated by certain volatile anesthetics (i.e., halothane, isoflurane, sevoflurane, desflurane, enflurane), either alone or in conjunction with a depolarizing muscle relaxant (specifically, succinylcholine). The triggering substances release calcium stores from the sarcoplasmic reticulum and may promote entry of calcium from the myoplasm, causing contracture of skeletal muscles, glycogenolysis, and increased cellular metabolism, resulting in production of heat and excess lactate. Affected individuals experience: acidosis, hypercapnia, tachycardia, hyperthermia, muscle rigidity, compartment syndrome, rhabdomyolysis with subsequent increase in serum creatine kinase (CK) concentration, hyperkalemia with a risk for cardiac arrhythmia or even arrest, and myoglobinuria with a risk for renal failure. In nearly all cases, the first manifestations of MH (tachycardia and tachypnea) occur in the operating room; however, MH may also occur in the early postoperative period. There is mounting evidence that some affected individuals will also develop MH with exercise and/or on exposure to hot environments. Without proper and prompt treatment with dantrolene sodium, mortality is extremely high.
Last Evaluated: May 30, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:201076930
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: May 30, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:201076930
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: May 30, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:201076930
Benign/Likely benign
Hetero
Gene:
LDB3
Variant:
c.349G>A
(p.Asp117Asn)
rsID: rs121908338
Ref Allele: G
Alt Allele: A
Freq: 0.6905%rare
CADD: 23.5
ClinVar Submissions (9)
Last Evaluated: Apr 01, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 9
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 10:86687073
OMIM Allelic Variant: 605906.0007
Last Evaluated: Apr 01, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 9
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 10:86687073
OMIM Allelic Variant: 605906.0007
Myofibrillar myopathy is characterized by slowly progressive weakness that can involve both proximal and distal muscles. Distal muscle weakness is present in about 80% of individuals and is more pronounced than proximal weakness in about 25%. A minority of individuals experience sensory symptoms, muscle stiffness, aching, or cramps. Peripheral neuropathy is present in about 20% of affected individuals. Overt cardiomyopathy is present in 15%-30%.
Last Evaluated: Apr 01, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 9
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 10:86687073
OMIM Allelic Variant: 605906.0007
Familial dilated cardiomyopathy is a genetic form of heart disease. It occurs when heart (cardiac) muscle becomes thin and weakened in at least one chamber of the heart, causing the open area of the chamber to become enlarged (dilated). As a result, the heart is unable to pump blood as efficiently as usual. To compensate, the heart attempts to increase the amount of blood being pumped through the heart, leading to further thinning and weakening of the cardiac muscle. Over time, this condition results in heart failure.It usually takes many years for symptoms of familial dilated cardiomyopathy to cause health problems. They typically begin in mid-adulthood, but can occur at any time from infancy to late adulthood. Signs and symptoms of familial dilated cardiomyopathy can include an irregular heartbeat (arrhythmia), shortness of breath (dyspnea), extreme tiredness (fatigue), fainting episodes (syncope), and swelling of the legs and feet. In some cases, the first sign of the disorder is sudden cardiac death. The severity of the condition varies among affected individuals, even in members of the same family.
Last Evaluated: Apr 01, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 9
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 10:86687073
OMIM Allelic Variant: 605906.0007
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Apr 01, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 9
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 10:86687073
OMIM Allelic Variant: 605906.0007
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Apr 01, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 9
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 10:86687073
OMIM Allelic Variant: 605906.0007
Conflicting/Uncertain
Hetero
Gene:
NPC2
Variant:
c.*295C>G
rsID: rs113587712
Ref Allele: G
Alt Allele: C
Freq: 0.7024%rare
CADD: 1.269
ClinVar Submissions (1)
Niemann-Pick disease type C (NPC) is a lipid storage disease that can present in infants, children, or adults. Neonates can present with ascites and severe liver disease from infiltration of the liver and/or respiratory failure from infiltration of the lungs. Other infants, without liver or pulmonary disease, have hypotonia and developmental delay. The classic presentation occurs in mid-to-late childhood with the insidious onset of ataxia, vertical supranuclear gaze palsy (VSGP), and dementia. Dystonia and seizures are common. Dysarthria and dysphagia eventually become disabling, making oral feeding impossible; death usually occurs in the late second or third decade from aspiration pneumonia. Adults are more likely to present with dementia or psychiatric symptoms.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 14:74479979
Conflicting/Uncertain
Hetero
Gene:
LTBP2
Variant:
c.1790-17G>A
rsID: rs147282006
Ref Allele: C
Alt Allele: T
Freq: 0.7112%rare
CADD: 0.153
ClinVar Submissions (1)
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jun 15, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 14:74536017
Likely benign
Hetero
Gene:
PMS1
Variant:
c.605G>A
(p.Arg202Lys)
rsID: rs2066459
Ref Allele: G
Alt Allele: A
Freq: 0.7454%rare
CADD: 19.13
ClinVar Submissions (3)
BRCA1- and BRCA2-associated hereditary breast and ovarian cancer syndrome (HBOC) is characterized by an increased risk for female and male breast cancer, ovarian cancer (includes fallopian tube and primary peritoneal cancers), and to a lesser extent other cancers such as prostate cancer, pancreatic cancer, and melanoma primarily in individuals with a BRCA2 pathogenic variant. The exact cancer risks differ slightly depending on whether HBOC is caused by a BRCA1 or BRCA2 pathogenic variant.
Last Evaluated: Dec 03, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 2:189843986
Lynch syndrome is characterized by an increased risk for colorectal cancer (CRC) and cancers of the endometrium, stomach, ovary, small bowel, hepatobiliary tract, urinary tract, brain, and skin. In individuals with Lynch syndrome the following lifetime risks for cancer are seen: CRC: 52%-82% (mean age at diagnosis 44-61 years). Endometrial cancer in females: 25%-60% (mean age at diagnosis 48-62 years). Gastric cancer: 6%-13% (mean age at diagnosis 56 years). Ovarian cancer: 4%-12% (mean age at diagnosis 42.5 years; ~30% are diagnosed < age 40 years). The risk for other Lynch syndrome-related cancers is lower, though substantially increased over general population rates.
Last Evaluated: Dec 03, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 2:189843986
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Dec 03, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 2:189843986
Conflicting/Uncertain
Hetero
Gene:
LAMA3
Variant:
c.4816-14C>T
rsID: rs72875942
Ref Allele: C
Alt Allele: T
Freq: 0.7502%rare
CADD: 8.55
ClinVar Submissions (1)
Junctional epidermolysis bullosa (JEB) is characterized by fragility of the skin and mucous membranes, manifest by blistering with little or no trauma. Blistering may be severe and granulation tissue can form on the skin around the oral and nasal cavities, fingers and toes, and internally around the upper airway. Blisters generally heal with no significant scarring. Broad classification of JEB includes JEB generalized severe and JEB generalized intermediate. In JEB generalized severe, blisters are present at birth or become apparent in the neonatal period. Congenital malformations of the urinary tract and bladder may also occur. In JEB generalized intermediate, the phenotype may be mild with blistering localized to hands, feet, knees, and elbows with or without renal or ureteral involvement. Some individuals never blister after the newborn period. Additional features shared by JEB and the other major forms of epidermolysis bullosa (EB) include congenital localized absence of skin (aplasia cutis congenita), milia, nail dystrophy, scarring alopecia, hypotrichosis, pseudosyndactyly, and other contractures.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 18:23951670
Laryngo-onycho-cutaneous (LOC) syndrome is a disorder that leads to abnormalities of the voicebox (laryngo-), finger- and toenails (onycho-), and skin (cutaneous). Many of the condition's signs and symptoms are related to the abnormal growth of granulation tissue in different parts of the body. This red, bumpy tissue is normally produced during wound healing and is usually replaced by skin cells as healing continues. However, in people with LOC syndrome, this tissue grows even when there is no major injury.One of the first symptoms in infants with LOC syndrome is a hoarse cry due to ulcers or overgrowth of granulation tissue in the voicebox (the larynx). Excess granulation tissue can also block the airways, leading to life-threatening breathing problems; as a result many affected individuals do not survive past childhood.In LOC syndrome, granulation tissue also grows in the eyes, specifically the conjunctiva, which are the moist tissues that line the eyelids and the white part of the eyes. Affected individuals often have impairment or complete loss of vision due to the tissue overgrowth.Another common feature of LOC syndrome is missing patches of skin (cutaneous erosions). The erosions heal slowly and may become infected. People with LOC syndrome can also have malformed nails and small, abnormal teeth. The hard, white material that forms the protective outer layer of each tooth (enamel) is thin, which contributes to frequent cavities.LOC syndrome is typically considered a subtype of another skin condition called junctional epidermolysis bullosa, which is characterized by fragile skin that blisters easily. While individuals with junctional epidermolysis bullosa can have some of the features of LOC syndrome, they do not usually have overgrowth of granulation tissue in the conjunctiva.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 18:23951670
Likely benign
Hetero
Gene:
HMCN1
Variant:
c.13040-3C>T
rsID: rs41317493
Ref Allele: C
Alt Allele: T
Freq: 0.7542%rare
CADD: 14.33
ClinVar Submissions (1)
A nonspecific term denoting degeneration of the retinal pigment epithelium and/or retinal photoreceptor cells of the macula lutea.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:186130504
Likely benign
Hetero
Gene:
CTNNA1
Variant:
c.1062+16654T>A
rsID: rs150431826
Ref Allele: T
Alt Allele: A
Freq: 0.7884%rare
CADD: 9.003
ClinVar Submissions (1)
The condition of a pattern of malignancies within a family, but not every individual's necessarily having the same neoplasm. Characteristically the tumor tends to occur at an earlier than average age, individuals may have more than one primary tumor, the tumors may be multicentric, usually more than 25 percent of the individuals in direct lineal descent from the proband are affected, and the cancer predisposition in these families behaves as an autosomal dominant trait with about 60 percent penetrance.
Last Evaluated: Dec 01, 2015
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 5:138844372
Likely benign
Hetero
Gene:
CTNNA1
Variant:
c.1062+16658G>T
rsID: rs114249793
Ref Allele: G
Alt Allele: T
Freq: 0.7892%rare
CADD: 10.25
ClinVar Submissions (1)
The condition of a pattern of malignancies within a family, but not every individual's necessarily having the same neoplasm. Characteristically the tumor tends to occur at an earlier than average age, individuals may have more than one primary tumor, the tumors may be multicentric, usually more than 25 percent of the individuals in direct lineal descent from the proband are affected, and the cancer predisposition in these families behaves as an autosomal dominant trait with about 60 percent penetrance.
Last Evaluated: Dec 01, 2015
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 5:138844376
Likely benign
Hetero
Gene:
RAD51C
Variant:
c.904+1374A>G
rsID: rs117829161
Ref Allele: A
Alt Allele: G
Freq: 0.7892%rare
CADD: 15.76
ClinVar Submissions (1)
The condition of a pattern of malignancies within a family, but not every individual's necessarily having the same neoplasm. Characteristically the tumor tends to occur at an earlier than average age, individuals may have more than one primary tumor, the tumors may be multicentric, usually more than 25 percent of the individuals in direct lineal descent from the proband are affected, and the cancer predisposition in these families behaves as an autosomal dominant trait with about 60 percent penetrance.
Last Evaluated: Dec 01, 2015
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 17:58722186
Likely benign
Hetero
Gene:
SNCAIP
Variant:
c.2125G>C
(p.Glu709Gln)
rsID: rs55712196
Ref Allele: G
Alt Allele: C
Freq: 0.7924%rare
CADD: 25.2
ClinVar Submissions (2)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 5:122450972
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 5:122450972
Likely benign
Hetero
Gene:
GLIS3
Variant:
c.171C>T
(p.Asn57=)
rsID: rs117802495
Ref Allele: G
Alt Allele: A
Freq: 0.7972%rare
CADD: 7.372
ClinVar Submissions (2)
Neonatal diabetes mellitus with congenital hypothyroidism (NDH) syndrome is characterized by intrauterine growth retardation and onset of nonimmune diabetes mellitus within the first few weeks of life. Other features include renal parenchymal disease, primarily renal cystic dysplasia, and hepatic disease, with hepatitis in some patients and hepatic fibrosis and cirrhosis in others. Facial dysmorphism, when present, consistently involves low-set ears, epicanthal folds, flat nasal bridge, long philtrum, and thin upper lip. Most patients exhibit developmental delay (Dimitri et al., 2015).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 9:4286255
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 9:4286255
Benign/Likely benign
Hetero
Gene:
NBN
Variant:
c.*1013G>A
rsID: rs13312984
Ref Allele: C
Alt Allele: T
Freq: 0.7996%rare
CADD: 1.253
ClinVar Submissions (1)
Nijmegen breakage syndrome (NBS) is characterized by progressive microcephaly, intrauterine growth retardation and short stature, recurrent sinopulmonary infections, an increased risk for cancer, and premature ovarian failure in females. Developmental milestones are attained at the usual time during the first year; however, borderline delays in development and hyperactivity may be observed in early childhood. Intellectual abilities tend to decline over time and most children tested after age seven years have mild to moderate intellectual disability. Recurrent pneumonia and bronchitis may result in respiratory failure and early death. Approximately 40% of affected individuals have developed malignancies before age 20 years, with the risk being highest for T-cell (55%) and B-cell lymphomas (45%). Other tumors include solid tumors (e.g., medulloblastoma, glioma, and rhabdomyosarcoma). Note, however, that much of what is reported about NBS is based on individuals who are homozygous for the single most common Eastern European pathogenic variant, c.657_661del5.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 8:89934569
Likely benign
Hetero
Gene:
TTN
Variant:
c.45488T>C
(p.Ile15163Thr)
rsID: rs72646809
Ref Allele: A
Alt Allele: G
Freq: 0.8012%rare
CADD: 25.7
ClinVar Submissions (7)
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:178607496
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:178607496
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:178607496
Udd distal myopathy is characterized by weakness of ankle dorsiflexion and inability to walk on the heels after age 35 years. Disease progression is slow and muscle weakness remains confined to the anterior tibial muscles. The long toe extensors become clinically involved after ten to 20 years, leading to foot drop and clumsiness when walking. In the mildest form, Udd distal myopathy can remain unnoticed even in the elderly.
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:178607496
Hereditary myopathy with early respiratory failure (HMERF) is a slowly progressive myopathy that typically begins in the third to fifth decades of life. The usual presenting findings are gait disturbance relating to distal leg weakness or nocturnal respiratory symptoms due to respiratory muscle weakness. Weakness eventually generalizes and affects both proximal and distal muscles. Most affected individuals require walking aids within a few years of onset; some progress to wheelchair dependence and require nocturnal noninvasive ventilatory support. The disease course varies even among individuals within the same family: some remain ambulant until their 70s whereas others may require ventilator support in their 40s.
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:178607496
A condition in which the myocardium is hypertrophied without an obvious cause. The hypertrophy is generally asymmetric and may be associated with obstruction of the ventricular outflow tract.
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:178607496
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:178607496
Limb-girdle muscular dystrophy is a term for a group of diseases that cause weakness and wasting of the muscles in the arms and legs. The muscles most affected are those closest to the body (proximal muscles), specifically the muscles of the shoulders, upper arms, pelvic area, and thighs.The severity, age of onset, and features of limb-girdle muscle dystrophy vary among the many subtypes of this condition and may be inconsistent even within the same family. Signs and symptoms may first appear at any age and generally worsen with time, although in some cases they remain mild.In the early stages of limb-girdle muscular dystrophy, affected individuals may have an unusual walking gait, such as waddling or walking on the balls of their feet, and may also have difficulty running. They may need to use their arms to press themselves up from a squatting position because of their weak thigh muscles. As the condition progresses, people with limb-girdle muscular dystrophy may eventually require wheelchair assistance.Muscle wasting may cause changes in posture or in the appearance of the shoulder, back, and arm. In particular, weak shoulder muscles tend to make the shoulder blades (scapulae) "stick out" from the back, a sign known as scapular winging. Affected individuals may also have an abnormally curved lower back (lordosis) or a spine that curves to the side (scoliosis). Some develop joint stiffness (contractures) that can restrict movement in their hips, knees, ankles, or elbows. Overgrowth (hypertrophy) of the calf muscles occurs in some people with limb-girdle muscular dystrophy.Weakening of the heart muscle (cardiomyopathy) occurs in some forms of limb-girdle muscular dystrophy. Some affected individuals experience mild to severe breathing problems related to the weakness of muscles needed for breathing. In some cases, the breathing problems are severe enough that affected individuals need to use a machine to help them breathe (mechanical ventilation).Intelligence is generally unaffected in limb-girdle muscular dystrophy; however, developmental delay and intellectual disability have been reported in rare forms of the disorder.
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:178607496
Salih myopathy is characterized by muscle weakness (manifest during the neonatal period or in early infancy) and delayed motor development; children acquire independent walking between age 20 months and four years. In the first decade of life, global motor performances are stable or tend to improve. Moderate joint and neck contractures and spinal rigidity may start in the first decade but become more obvious in the second decade. Scoliosis develops after age 11 years. Cardiac dysfunction starts between ages five and 16 years, progresses rapidly, and leads to death between ages eight and 20 years, usually from heart rhythm disturbances.
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:178607496
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:178607496
Benign/Likely benign
Hetero
Gene:
PITPNM3
Variant:
c.*576T>C
rsID: rs570375031
Ref Allele: A
Alt Allele: G
Freq: 0.8051%rare
CADD: 6.387
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 17:6454762
Likely benign
Hetero
Gene:
BMPER
Variant:
c.774T>G
(p.Ala258=)
rsID: rs117988035
Ref Allele: T
Alt Allele: G
Freq: 0.8251%rare
CADD: 0.275
ClinVar Submissions (1)
Diaphanospondylodysostosis is a rare, recessively inherited, perinatal lethal skeletal disorder. The primary skeletal characteristics include small chest, abnormal vertebral segmentation, and posterior rib gaps containing incompletely differentiated mesenchymal tissue. Consistent craniofacial features include ocular hypertelorism, epicanthal folds, depressed nasal bridge with short nose, and low-set ears. The most commonly described extraskeletal finding is nephroblastomatosis with cystic kidneys, but other visceral findings have been described in some cases (summary by Funari et al., 2010).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 7:34051958
Conflicting/Uncertain
Hetero
Gene:
COQ8B
Variant:
c.1119C>T
(p.Phe373=)
rsID: rs56056214
Ref Allele: G
Alt Allele: A
Freq: 0.833%rare
CADD: 10.93
ClinVar Submissions (2)
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jul 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 19:40700091
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 19:40700091
Benign
Hetero
Gene:
NPHS1
Variant:
c.881C>T
(p.Thr294Ile)
rsID: rs113825926
Ref Allele: G
Alt Allele: A
Freq: 0.8338%rare
CADD: 9.689
ClinVar Submissions (2)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 03, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 19:35849107
Benign
Hetero
Gene:
AP4M1
Variant:
c.1002C>T
(p.Leu334=)
rsID: rs140843407
Ref Allele: C
Alt Allele: T
Freq: 0.8617%rare
CADD: 2.865
ClinVar Submissions (3)
AP-4-associated hereditary spastic paraplegia (HSP), also known as AP-4 deficiency syndrome, is a group of neurodegenerative disorders characterized by a progressive, complex spastic paraplegia with onset typically in infancy or early childhood. Early-onset hypotonia evolves into progressive lower-extremity spasticity. The majority of children become non-ambulatory and usually wheelchair bound. Over time spasticity progresses to involve the upper extremities, resulting in a spastic tetraplegia. Associated complications include dysphagia, contractures, foot deformities, dysregulation of bladder and bowel function, and a pseudobulbar affect. About 50% of affected individuals have seizures. Postnatal microcephaly (usually in the -2SD to -3SD range) is common. All have global developmental delay. Speech development is significantly impaired and many affected individuals remain nonverbal. Intellectual disability in older children is usually moderate to severe.
Last Evaluated: Jul 12, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 7:100106268
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 12, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 7:100106268
Benign
Hetero
Gene:
COL12A1
Variant:
c.5508G>A
(p.Thr1836=)
rsID: rs77425231
Ref Allele: C
Alt Allele: T
Freq: 0.8744%rare
CADD: 0.565
ClinVar Submissions (2)
Last Evaluated: Dec 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 6:75134742
Last Evaluated: Dec 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 6:75134742
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Dec 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 6:75134742
Benign
Hetero
Gene:
AP1S3
Variant:
c.11T>G
(p.Phe4Cys)
rsID: rs116107386
Ref Allele: A
Alt Allele: C
Freq: 0.8832%rare
CADD: 31
ClinVar Submissions (1)
Generalized pustular psoriasis (GPP) is a severe form of a skin disorder called psoriasis. GPP and other forms of psoriasis are caused by abnormal inflammation. Inflammation is a normal immune system response to injury and foreign invaders (such as bacteria). However, when inflammation is abnormal and uncontrolled, it can damage the body's tissues and organs. Individuals with GPP have repeated episodes in which large areas of skin become red and inflamed and develop small pus-filled blisters (pustules). The skin problems can be accompanied by fever, extreme tiredness (fatigue), muscle weakness, an increased number of white blood cells, and other signs of inflammation throughout the body (systemic inflammation). The inflammation problems subside and reappear often. Episodes can be triggered by infection, exposure to or withdrawal from certain medications, menstruation, or pregnancy, although the trigger is often unknown. GPP can be life-threatening if not treated.While many affected individuals have features only of GPP (called GPP alone), some develop features of another skin condition called psoriasis vulgaris (PV), either before or after GPP appears. PV, the most common form of psoriasis, is characterized by red, scaly patches of skin (plaques) on parts of the body.
Last Evaluated: May 01, 2014
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: risk factor
Assembly: GRCh38
Chromosome/Position: 2:223777862
OMIM Allelic Variant: 615781.0002
Hetero
Gene:
SCN1A
Variant:
c.5418G>A
(p.Glu1806=)
rsID: rs140237315
Ref Allele: C
Alt Allele: T
Freq: 0.9166%rare
CADD: 19.36
ClinVar Submissions (7)
A neurological disorder characterized by recurring seizures presenting within the first three months of life and progressive cerebral dysfunction.
Last Evaluated: Aug 04, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:165991857
A brain disorder characterized by episodes of abnormally increased neuronal discharge resulting in transient episodes of sensory or motor neurological dysfunction, or psychic dysfunction. These episodes may or may not be associated with loss of consciousness or convulsions.
Last Evaluated: Aug 04, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:165991857
Familial hemiplegic migraine (FHM) falls within the category of migraine with aura. In migraine with aura (including familial hemiplegic migraine) the neurologic symptoms of aura are unequivocally localizable to the cerebral cortex or brain stem and include visual disturbance (most common), sensory loss (e.g., numbness or paresthesias of the face or an extremity), and dysphasia (difficulty with speech); FHM must include motor involvement, i.e., hemiparesis (weakness of an extremity). Hemiparesis occurs with at least one other symptom during FHM aura. Neurologic deficits with FHM attacks can be prolonged for hours to days and may outlast the associated migrainous headache. FHM is often earlier in onset than typical migraine, frequently beginning in the first or second decade; the frequency of attacks tends to decrease with age. Approximately 40%-50% of families with FHM1 have cerebellar signs ranging from nystagmus to progressive, usually late-onset mild ataxia. Cerebral infarction and death have rarely been associated with hemiplegic migraine.
Last Evaluated: Aug 04, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:165991857
Last Evaluated: Aug 04, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:165991857
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 04, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:165991857
Benign/Likely benign
Hetero
Gene:
SERPINA1
Variant:
c.1068C>T
(p.Ala356=)
rsID: rs9630
Ref Allele: G
Alt Allele: A
Freq: 0.931%rare
CADD: 7.4
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 14:94378638
Benign
Hetero
Gene:
PDSS1
Variant:
c.-29C>T
rsID: rs537781419
Ref Allele: C
Alt Allele: T
Freq: 0.958%rare
CADD: 15.47
ClinVar Submissions (2)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 2
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 10:26697683
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 2
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 10:26697683
Conflicting/Uncertain
Hetero
Gene:
IFT122
Variant:
c.2096A>C
(p.Glu699Ala)
rsID: rs144397126
Ref Allele: A
Alt Allele: C
Freq: 0.9588%rare
CADD: 22.4
ClinVar Submissions (1)
Cranioectodermal dysplasia (CED), a ciliopathy also known as Sensenbrenner syndrome, is a multisystem disorder with skeletal involvement (narrow thorax, shortened proximal limbs, and brachydactyly), ectodermal features (widely-spaced hypoplastic teeth, hypodontia, sparse hair, skin laxity, abnormal nails), joint laxity, growth retardation, and characteristic facial features (frontal bossing, low-set simple ears, high forehead, telecanthus/epicanthus, full cheeks, everted lower lip). Most affected children develop nephronophthisis that often leads to end-stage renal disease (ESRD) in infancy or childhood, a major cause of morbidity and mortality. Hepatic fibrosis and retinal dystrophy, other manifestations of ciliopathies, are also observed. Dolichocephaly, often secondary to sagittal craniosynostosis, is a primary manifestation that distinguishes CED from most other ciliopathies. Brain malformations and developmental delay may also occur.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 3:129488348
Likely benign
Hetero
Gene:
DCLRE1C
Variant:
c.457G>A
(p.Gly153Arg)
rsID: rs41297018
Ref Allele: C
Alt Allele: T
Freq: 0.9708%rare
CADD: 24.2
ClinVar Submissions (5)
Last Evaluated: Mar 09, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 10:14935470
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Mar 09, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 10:14935470
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 09, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 10:14935470
Benign/Likely benign
Hetero
Gene:
GLIS2
Variant:
c.*916G>A
rsID: rs72766567
Ref Allele: G
Alt Allele: A
Freq: 0.9724%rare
CADD: 5.502
ClinVar Submissions (1)
The nephronophthisis (NPH) phenotype is characterized by reduced renal concentrating ability, chronic tubulointerstitial nephritis, cystic renal disease, and progression to end-stage renal disease (ESRD) before age 30 years. Three age-based clinical subtypes are recongnized: infantile, juvenile, and adolescent/adult. Infantile NPH can present in utero with oligohydramnios sequence (limb contractures, pulmonary hypoplasia and facial dysmorphisms) or postnatally with renal manifestations that progress to ESRD before age 3 years. Juvenile NPH, the most prevalent subtype, typically presents with polydipsia and polyuria, growth retardation, chronic iron-resistant anemia, or other findings related to chronic kidney disease (CKD). Hypertension is typically absent due to salt wasting. ESRD develops at a median age of 13 years. Ultrasound findings are increased echogenicity, reduced corticomedullary differentiation, and renal cysts (in 50% of affected individuals). Histologic findings include tubulointerstitial fibrosis, thickened and disrupted tubular basement membrane, sporadic corticomedullary cysts, and normal or reduced kidney size. Adolescent/ adult NPH is clinically similar to juvenile NPH, but ESRD develops at a median age of 19 years. Within a subtype inter- and intrafamilial variability in rate of progression to ESRD is considerable. Approximately 80%-90% of individuals with the NPH phenotype have no extrarenal features (i.e., they have isolated NPH); ~10%-20% have extrarenal manifestations that constitute a recognizable syndrome (e.g., Joubert syndrome, Bardet-Biedl syndrome, Jeune syndrome and related skeletal disorders, Meckel-Gruber syndrome, Senior-Løken syndrome, Leber congenital amaurosis, COACH syndrome, and oculomotor apraxia, Cogan type).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 16:4338440
Conflicting/Uncertain
Hetero
Gene:
SNTA1
Variant:
c.828G>A
(p.Lys276=)
rsID: rs35938843
Ref Allele: C
Alt Allele: T
Freq: 0.9859%rare
CADD: 8.164
ClinVar Submissions (3)
Last Evaluated: Jul 10, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 20:33412656
A condition that is characterized by episodes of fainting (SYNCOPE) and varying degree of ventricular arrhythmia as indicated by the prolonged QT interval. The inherited forms are caused by mutation of genes encoding cardiac ion channel proteins. The two major forms are ROMANO-WARD SYNDROME and JERVELL-LANGE NIELSEN SYNDROME.
Last Evaluated: Jul 10, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 20:33412656
Long QT syndrome (LQTS) is a cardiac electrophysiologic disorder, characterized by QT prolongation and T-wave abnormalities on the ECG that are associated with tachyarrhythmias, typically the ventricular tachycardia torsade de pointes (TdP). TdP is usually self-terminating, thus causing a syncopal event, the most common symptom in individuals with LQTS. Such cardiac events typically occur during exercise and emotional stress, less frequently during sleep, and usually without warning. In some instances, TdP degenerates to ventricular fibrillation and causes aborted cardiac arrest (if the individual is defibrillated) or sudden death. Approximately 50% of untreated individuals with a pathogenic variant in one of the genes associated with LQTS have symptoms, usually one to a few syncopal events. While cardiac events may occur from infancy through middle age, they are most common from the preteen years through the 20s. Some types of LQTS are associated with a phenotype extending beyond cardiac arrhythmia. In addition to the prolonged QT interval, associations include muscle weakness and facial dysmorphism in Andersen-Tawil syndrome (LQTS type 7), hand/foot, facial, and neurodevelopmental features in Timothy syndrome (LQTS type 8), and profound sensorineural hearing loss in Jervell and Lange-Nielson syndrome.
Last Evaluated: Jul 10, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 20:33412656
Conflicting/Uncertain
Hetero
Below are uncommon mutations (frequency between 1% and 5%) found in ClinVar. The data presented has no guarantees of reporting accuracy. Heterozygous variants are repoted as yellow and homozygous variants as red. A red or yellow variant does not necessarily mean one has or carries a condition or disease. This is for research and educational purposes only.
Gene:
NKX3-2
Variant:
c.351C>G
(p.Gly117=)
rsID: rs145908097
Ref Allele: G
Alt Allele: C
Freq: 1.0178%uncommon
CADD: 8.087
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Nov 09, 2015
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 4:13544064
Benign
Hetero
Gene:
PITPNM3
Variant:
c.2156+20C>T
rsID: rs75323938
Ref Allele: G
Alt Allele: A
Freq: 1.0361%uncommon
CADD: 8.725
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 17:6464150
Benign
Hetero
Gene:
COQ8B
Variant:
c.1210-10G>A
rsID: rs77801349
Ref Allele: C
Alt Allele: T
Freq: 1.0592%uncommon
CADD: 0.271
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 08, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 19:40693047
Benign
Hetero
Gene:
SCN4A
Variant:
c.2717G>C
(p.Ser906Thr)
rsID: rs41280102
Ref Allele: C
Alt Allele: G
Freq: 1.0751%uncommon
CADD: 8.037
ClinVar Submissions (8)
Last Evaluated: Jan 03, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:63951560
Last Evaluated: Jan 03, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:63951560
Hyperkalemic periodic paralysis (hyperPP) is characterized by attacks of flaccid limb weakness (which may also include weakness of the muscles of the eyes, throat, and trunk), hyperkalemia (serum potassium concentration >5 mmol/L) or an increase of serum potassium concentration of at least 1.5 mmol/L during an attack of weakness and/or provoking/worsening of an attack by oral potassium intake, normal serum potassium between attacks, and onset before age 20 years. Although the absence of paramyotonia (muscle stiffness aggravated by cold and exercise) was originally postulated as a means of distinguishing hyperPP from paramyotonia congenita (PMC), approximately 45% of individuals with hyperPP have paramyotonia. In approximately half of affected individuals, attacks of flaccid muscle weakness begin in the first decade of life, with 25% reporting their first attack at age ten years or older. Initially infrequent, the attacks then increase in frequency and severity over time until approximately age 50 years, after which the frequency of attacks declines considerably. Potassium-rich food or rest after exercise may precipitate an attack. A cold environment and emotional stress provoke or worsen the attacks. A spontaneous attack commonly starts in the morning before breakfast, lasts for 15 minutes to one hour, and then disappears. Cardiac arrhythmia or respiratory insufficiency usually does not occur during attacks. Between attacks, approximately half of individuals with hyperPP have mild myotonia (muscle stiffness) that does not impede voluntary movements. More than 80% of individuals with hyperPP older than 40 years report permanent muscle weakness and about one third develop a chronic progressive myopathy.
Last Evaluated: Jan 03, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:63951560
Hypokalemic periodic paralysis (hypoPP) is a condition in which affected individuals may experience paralytic episodes with concomitant hypokalemia (serum potassium <3.5 mmol/L). The paralytic attacks are characterized by decreased muscle tone (flaccidity) more marked proximally than distally with normal to decreased deep tendon reflexes. The episodes develop over minutes to hours and last several minutes to several days with spontaneous recovery. Some individuals have only one episode in a lifetime; more commonly, crises occur repeatedly: daily, weekly, monthly, or less often. The major triggering factors are cessation of effort following strenuous exercise and carbohydrate-rich evening meals. Additional triggers can include cold, stress/excitement/fear, salt intake, prolonged immobility, use of glucosteroids or alcohol, and anesthetic procedures. The age of onset of the first attack ranges from two to 30 years; the duration of paralytic episodes ranges from one to 72 hours with an average of nearly 24 hours. Long-lasting interictal muscle weakness may occur in some affected individuals and in some stages of the disease and in myopathic muscle changes. A myopathy may occur independent of paralytic symptoms and may be the sole manifestation of hypoPP.
Last Evaluated: Jan 03, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:63951560
Paramyotonia congenita is a disorder that affects muscles used for movement (skeletal muscles). Beginning in infancy or early childhood, people with this condition experience bouts of sustained muscle tensing (myotonia) that prevent muscles from relaxing normally. Myotonia causes muscle stiffness that typically appears after exercise and can be induced by muscle cooling. This stiffness chiefly affects muscles in the face, neck, arms, and hands, although it can also affect muscles used for breathing and muscles in the lower body. Unlike many other forms of myotonia, the muscle stiffness associated with paramyotonia congenita tends to worsen with repeated movements.Most people—even those without muscle disease—feel that their muscles do not work as well when they are cold. This effect is dramatic in people with paramyotonia congenita. Exposure to cold initially causes muscle stiffness in these individuals, and prolonged cold exposure leads to temporary episodes of mild to severe muscle weakness that may last for several hours at a time. Some older people with paramyotonia congenita develop permanent muscle weakness that can be disabling.
Last Evaluated: Jan 03, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:63951560
In a report on the 37th ENMC Workshop, Rudel and Lehmann-Horn (1997) stated that the sodium channelopathies can be divided into 3 different forms: paramyotonia, potassium-aggravated myotonia, and periodic paralysis. Potassium-aggravated myotonia includes mild myotonia fluctuans, severe myotonia permanens, and acetazolamide-responsive myotonia.
Last Evaluated: Jan 03, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:63951560
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jan 03, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:63951560
Benign/Likely benign
Hetero
Gene:
CCDC33
Variant:
c.1829C>T
(p.Pro610Leu)
rsID: rs77396610
Ref Allele: C
Alt Allele: T
Freq: 1.0767%uncommon
CADD: 16.52
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 06, 2015
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 15:74332736
Likely benign
Hetero
Gene:
RECQL4
Variant:
c.212A>G
(p.Glu71Gly)
rsID: rs34642881
Ref Allele: T
Alt Allele: C
Freq: 1.0783%uncommon
CADD: 23.1
ClinVar Submissions (4)
Baller-Gerold syndrome (BGS) can be suspected at birth in an infant with craniosynostosis and upper limb abnormality. The coronal suture is most commonly affected; the metopic, lambdoid, and sagittal sutures may also be involved alone or in combination. Upper limb abnormality can include a combination of thumb hypo- or aplasia and radial hypo- or aplasia and may be asymmetric. Malformation or absence of carpal or metacarpal bones has also been described. Skin lesions may appear anytime within the first few years after birth, typically beginning with erythema of the face and extremities and evolving into poikiloderma. Slow growth is apparent in infancy with eventual height and length typically at 4 SD below the mean.
Last Evaluated: Aug 10, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 8:144517415
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 10, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 8:144517415
Benign
Hetero
Gene:
CHMP2B
Variant:
c.-151C>A
rsID: rs77328592
Ref Allele: C
Alt Allele: A
Freq: 1.0879%uncommon
CADD: 14.41
ClinVar Submissions (1)
Frontotemporal dementia (FTD) refers to a clinical manifestation of the pathologic finding of frontotemporal lobar degeneration (FTLD). FTD, the most common subtype of FTLD, is a behavioral variant characterized by changes in social and personal conduct with loss of volition, executive dysfunction, loss of abstract thought, and decreased speech output. A second clinical subtype of FTLD is 'semantic dementia,' characterized by specific loss of comprehension of language and impaired facial and object recognition. A third clinical subtype of FTLD is 'primary progressive aphasia' (PPA), characterized by a reduction in speech production, speech errors, and word retrieval difficulties resulting in mutism and an inability to communicate. All subtypes have relative preservation of memory, at least in the early stages. FTLD is often associated with parkinsonism or motor neuron disease (MND) resembling amyotrophic lateral sclerosis (ALS; 105400) (reviews by Tolnay and Probst, 2002 and Mackenzie and Rademakers, 2007). Mackenzie et al. (2009, 2010) provided a classification of FTLD subtypes according to the neuropathologic findings (see PATHOGENESIS below). Clinical Variability of Tauopathies Tauopathies comprise a clinically variable group of neurodegenerative diseases characterized neuropathologically by accumulation of abnormal MAPT-positive inclusions in nerve and/or glial cells. In addition to frontotemporal dementia, semantic dementia, and PPA, different clinical syndromes with overlapping features have been described, leading to confusion in the terminology (Tolnay and Probst, 2002). Other terms used historically include parkinsonism and dementia with pallidopontonigral degeneration (PPND) (Wszolek et al., 1992); disinhibition-dementia-parkinsonism-amyotrophy complex (DDPAC) (Lynch et al., 1994); frontotemporal dementia with parkinsonism (FLDEM) (Yamaoka et al., 1996); and multiple system tauopathy with presenile dementia (MSTD) (Spillantini et al., 1997). These disorders are characterized by variable degrees of frontal lobe dementia, parkinsonism, motor neuron disease, and amyotrophy. Other neurodegenerative associated with mutations in the MAPT gene include Pick disease (172700) and progressive supranuclear palsy (PSP; 601104), Inherited neurodegenerative tauopathies linked to chromosome 17 and caused by mutation in the MAPT gene have also been collectively termed 'FTDP17' (Lee et al., 2001). Kertesz (2003) suggested the term 'Pick complex' to represent the overlapping syndromes of FTD, primary progressive aphasia (PPA), corticobasal degeneration (CBD), PSP, and FTD with motor neuron disease. He noted that frontotemporal dementia may also be referred to as 'clinical Pick disease' and that the term 'Pick disease' should be restricted to the pathologic finding of Pick bodies. Genetic Heterogeneity of Frontotemporal Lobar Degeneration Mutations in several different genes can cause frontotemporal dementia and frontotemporal lobar degeneration, with or without motor neuron disease. See FTLD with TDP43 inclusions (607485), caused by mutation in the GRN gene (138945) on chromosome 17q21; FTLD mapping to chromosome 3 (600795), caused by mutation in the CHMP2B gene (609512); inclusion body myopathy with Paget disease and FTD (IBMPFD; 167320), caused by mutation in the VCP gene (601023) on chromosome 9p13; ALS6 (608030), caused by mutation in the FUS gene (137070) on 16p11; ALS10 (612069), caused by mutation in the TARDBP gene (605078) on 1p36; and FTDALS (105550), caused by mutation in the C9ORF72 gene (614260) on 9p. In 1 family with FTD, a mutation was identified in the presenilin-1 gene (PSEN1; 104311) on chromosome 14, which is usually associated with a familial form of early-onset Alzheimer disease (AD3; 607822).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 3:87227372
Likely benign
Hetero
Gene:
BRCA2
Variant:
c.316+860G>A
rsID: rs11571589
Ref Allele: G
Alt Allele: A
Freq: 1.1181%uncommon
CADD: 2.239
ClinVar Submissions (1)
BRCA1- and BRCA2-associated hereditary breast and ovarian cancer syndrome (HBOC) is characterized by an increased risk for female and male breast cancer, ovarian cancer (includes fallopian tube and primary peritoneal cancers), and to a lesser extent other cancers such as prostate cancer, pancreatic cancer, and melanoma primarily in individuals with a BRCA2 pathogenic variant. The exact cancer risks differ slightly depending on whether HBOC is caused by a BRCA1 or BRCA2 pathogenic variant.
Last Evaluated: Jan 12, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 13:32320185
Expert Reviewed Benign
Hetero
Gene:
SCN8A
Variant:
c.*1405C>T
rsID: rs141823772
Ref Allele: C
Alt Allele: T
Freq: 1.1516%uncommon
CADD: 16.36
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 12:51808834
Likely benign
Hetero
Gene:
ABCB7
Variant:
c.249+1G>A
rsID: rs61323727
Ref Allele: C
Alt Allele: T
Freq: 1.1516%uncommon
ClinVar Submissions (3)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: X:75114753
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: X:75114753
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: X:75114753
Conflicting/Uncertain
Homo
Gene:
NIN
Variant:
c.819C>T
(p.Phe273=)
rsID: rs61755581
Ref Allele: G
Alt Allele: A
Freq: 1.189%uncommon
CADD: 9.1
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 14:50772463
Likely benign
Hetero
Gene:
GAA
Variant:
c.1726G>A
(p.Gly576Ser)
rsID: rs1800307
Ref Allele: G
Alt Allele: A
Freq: 1.1898%uncommon
CADD: 26.2
ClinVar Submissions (8)
Pompe disease is classified by age of onset, organ involvement, severity, and rate of progression. Infantile-onset Pompe disease (IOPD; individuals with onset before age 12 months with cardiomyopathy) may be apparent in utero but more typically onset is at the median age of four months with hypotonia, generalized muscle weakness, feeding difficulties, failure to thrive, respiratory distress, and hypertrophic cardiomyopathy. Without treatment by enzyme replacement therapy (ERT), IOPD commonly results in death by age two years from progressive left ventricular outflow obstruction and respiratory insufficiency. Late-onset Pompe disease (LOPD; including: (a) individuals with onset before age 12 months without cardiomyopathy; and (b) all individuals with onset after age 12 months) is characterized by proximal muscle weakness and respiratory insufficiency; clinically significant cardiac involvement is uncommon.
Last Evaluated: Jul 09, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign, other
Assembly: GRCh38
Chromosome/Position: 17:80112072
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jul 09, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign, other
Assembly: GRCh38
Chromosome/Position: 17:80112072
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 09, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign, other
Assembly: GRCh38
Chromosome/Position: 17:80112072
Benign/Likely benign, other
Hetero
Gene:
TNFRSF14
Variant:
c.348C>T
(p.Asn116=)
rsID: rs2234162
Ref Allele: C
Alt Allele: T
Freq: 1.1994%uncommon
CADD: 0.52
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Sep 19, 2013
Review Status: no assertion provided
Number of Submitters: 1
Clinical Significance: not provided
Assembly: GRCh38
Chromosome/Position: 1:2559866
Hetero
Gene:
MSH2
Variant:
g.114271G>A
rsID: rs116117580
Ref Allele: G
Alt Allele: A
Freq: 1.1994%uncommon
CADD: 0.013
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Sep 19, 2013
Review Status: no assertion provided
Number of Submitters: 1
Clinical Significance: not provided
Assembly: GRCh38
Chromosome/Position: 2:47512394
Hetero
Gene:
NBEAL2
Variant:
c.5661A>C
(p.Pro1887=)
rsID: rs140548682
Ref Allele: A
Alt Allele: C
Freq: 1.2217%uncommon
CADD: 4.426
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 3:47003250
Benign
Hetero
Gene:
SMAD9
Variant:
c.*2905T>C
rsID: rs118015060
Ref Allele: A
Alt Allele: G
Freq: 1.2296%uncommon
CADD: 6.88
ClinVar Submissions (1)
Pulmonary arterial hypertension (PAH) is characterized by widespread obstruction and obliteration of the smallest pulmonary arteries. When a sufficient number of vessels are occluded, the resistance to blood flow through the lungs increases, and the right ventricle attempts to compensate by generating higher pressure to maintain pulmonary blood flow. When the right ventricle can no longer compensate for the increased resistance, progressive heart failure ensues. Initial symptoms include dyspnea (60%), fatigue (19%), syncope (8%), chest pain (7%), palpitations (5%), and leg edema (3%). All ages are affected, but the mean age at diagnosis is 36 years. Mean survival after diagnosis is 2.8 years; current therapy does improve clinical function but has modest effect on survival. The term "heritable PAH" (HPAH) includes familial PAH (PAH that occurs in two or more family members) and simplex PAH (i.e., a single occurrence in a family) when a pathogenic variant has been identified. Most heritable PAH (75%) is caused by a pathogenic variant in BMPR2; pathogenic variants in other genes (i.e., ACVRL1, KCNK3, CAV1, SMAD9, BMPR1B) are considerably less common (1%-3%). HPAH has identical symptoms, signs, and histology as PAH of unknown cause. The time from onset of symptoms to diagnosis may be shorter in individuals with familial PAH, possibly because of familial awareness of the disease. Three retrospective studies suggest that persons with PAH who have a BMPR2 pathogenic variant exhibit more severe disease.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 13:36845771
Likely benign
Hetero
Gene:
SLC4A1
Variant:
c.118G>A
(p.Glu40Lys)
rsID: rs45562031
Ref Allele: C
Alt Allele: T
Freq: 1.2304%uncommon
CADD: 11.61
ClinVar Submissions (6)
A condition of inadequate circulating red blood cells (ANEMIA) or insufficient HEMOGLOBIN due to premature destruction of red blood cells (ERYTHROCYTES).
Last Evaluated: Dec 15, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 17:44261625
OMIM Allelic Variant: 109270.0004
Cryohydrocytosis is an exceedingly rare condition characterized by a mild stomatocytic hemolytic state with hyperbilirubinemia. A hallmark of this condition is that red blood cells (RBCs) lyse on storage at 4 degrees centigrade. RBC cation permeability is increased at 37 degrees centigrade, and the cells also accumulate sodium in the cold (summary by Coles et al., 1999). Patients present with fatigue, mild anemia, and pseudohyperkalemia due to a potassium leak from the RBCs (summary by Bogdanova et al., 2010). For a discussion of clinical and genetic heterogeneity of the hereditary stomatocytoses, see 194380.
Last Evaluated: Dec 15, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 17:44261625
OMIM Allelic Variant: 109270.0004
Hereditary spherocytosis is a condition that affects red blood cells. People with this condition typically experience a shortage of red blood cells (anemia), yellowing of the eyes and skin (jaundice), and an enlarged spleen (splenomegaly). Most newborns with hereditary spherocytosis have severe anemia, although it improves after the first year of life. Splenomegaly can occur anytime from early childhood to adulthood. About half of affected individuals develop hard deposits in the gallbladder called gallstones, which typically occur from late childhood to mid-adulthood.There are four forms of hereditary spherocytosis, which are distinguished by the severity of signs and symptoms. They are known as the mild form, the moderate form, the moderate/severe form, and the severe form. It is estimated that 20 to 30 percent of people with hereditary spherocytosis have the mild form, 60 to 70 percent have the moderate form, 10 percent have the moderate/severe form, and 3 to 5 percent have the severe form.People with the mild form may have very mild anemia or sometimes have no symptoms. People with the moderate form typically have anemia, jaundice, and splenomegaly. Many also develop gallstones. The signs and symptoms of moderate hereditary spherocytosis usually appear in childhood. Individuals with the moderate/severe form have all the features of the moderate form but also have severe anemia. Those with the severe form have life-threatening anemia that requires frequent blood transfusions to replenish their red blood cell supply. They also have severe splenomegaly, jaundice, and a high risk for developing gallstones. Some individuals with the severe form have short stature, delayed sexual development, and skeletal abnormalities.
Last Evaluated: Dec 15, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 17:44261625
OMIM Allelic Variant: 109270.0004
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Dec 15, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 17:44261625
OMIM Allelic Variant: 109270.0004
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Dec 15, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 17:44261625
OMIM Allelic Variant: 109270.0004
Moderate clinical importance, Uncertain pathogenic — Rare and reported to cause hemolytic anemia in a recessive manner, although insufficient data is published to establish statistical significance. Polyphen 2 predicts a benign effect.
Clinically Significant Conflicting/Uncertain
Hetero
Gene:
CNGA1
Variant:
c.95G>A
(p.Arg32Gln)
rsID: rs76537883
Ref Allele: C
Alt Allele: T
Freq: 1.2591%uncommon
CADD: 23.2
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 4:47952607
Conflicting/Uncertain
Hetero
Gene:
TTN
Variant:
c.72079G>C
(p.Asp24027His)
rsID: rs56307213
Ref Allele: C
Alt Allele: G
Freq: 1.283%uncommon
CADD: 25.6
ClinVar Submissions (7)
Last Evaluated: Aug 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:178566349
Last Evaluated: Aug 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:178566349
Limb-girdle muscular dystrophy is a term for a group of diseases that cause weakness and wasting of the muscles in the arms and legs. The muscles most affected are those closest to the body (proximal muscles), specifically the muscles of the shoulders, upper arms, pelvic area, and thighs.The severity, age of onset, and features of limb-girdle muscle dystrophy vary among the many subtypes of this condition and may be inconsistent even within the same family. Signs and symptoms may first appear at any age and generally worsen with time, although in some cases they remain mild.In the early stages of limb-girdle muscular dystrophy, affected individuals may have an unusual walking gait, such as waddling or walking on the balls of their feet, and may also have difficulty running. They may need to use their arms to press themselves up from a squatting position because of their weak thigh muscles. As the condition progresses, people with limb-girdle muscular dystrophy may eventually require wheelchair assistance.Muscle wasting may cause changes in posture or in the appearance of the shoulder, back, and arm. In particular, weak shoulder muscles tend to make the shoulder blades (scapulae) "stick out" from the back, a sign known as scapular winging. Affected individuals may also have an abnormally curved lower back (lordosis) or a spine that curves to the side (scoliosis). Some develop joint stiffness (contractures) that can restrict movement in their hips, knees, ankles, or elbows. Overgrowth (hypertrophy) of the calf muscles occurs in some people with limb-girdle muscular dystrophy.Weakening of the heart muscle (cardiomyopathy) occurs in some forms of limb-girdle muscular dystrophy. Some affected individuals experience mild to severe breathing problems related to the weakness of muscles needed for breathing. In some cases, the breathing problems are severe enough that affected individuals need to use a machine to help them breathe (mechanical ventilation).Intelligence is generally unaffected in limb-girdle muscular dystrophy; however, developmental delay and intellectual disability have been reported in rare forms of the disorder.
Last Evaluated: Aug 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:178566349
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:178566349
Benign
Hetero
Gene:
PSEN1
Variant:
c.953A>G
(p.Glu318Gly)
rsID: rs17125721
Ref Allele: A
Alt Allele: G
Freq: 1.2878%uncommon
CADD: 23.6
ClinVar Submissions (7)
Acne inversa is a chronic inflammatory disease of the hair follicles whose characteristic features include draining sinuses, painful skin abscesses, and disfiguring scars. Manifestations typically appear after puberty. Familial acne inversa is genetically heterogeneous (summary by Wang et al., 2010). For a general phenotypic description and a discussion of genetic heterogeneity of familial acne inversa, see 142690.
Last Evaluated: Sep 22, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 14:73206470
Alzheimer disease is a degenerative disease of the brain that causes dementia, which is a gradual loss of memory, judgment, and ability to function. This disorder usually appears in people older than age 65, but less common forms of the disease appear earlier in adulthood.Memory loss is the most common sign of Alzheimer disease. Forgetfulness may be subtle at first, but the loss of memory worsens over time until it interferes with most aspects of daily living. Even in familiar settings, a person with Alzheimer disease may get lost or become confused. Routine tasks such as preparing meals, doing laundry, and performing other household chores can be challenging. Additionally, it may become difficult to recognize people and name objects. Affected people increasingly require help with dressing, eating, and personal care.As the disorder progresses, some people with Alzheimer disease experience personality and behavioral changes and have trouble interacting in a socially appropriate manner. Other common symptoms include agitation, restlessness, withdrawal, and loss of language skills. People with this disease usually require total care during the advanced stages of the disease. Affected individuals usually survive 8 to 10 years after the appearance of symptoms, but the course of the disease can range from 1 to 25 years. Death usually results from pneumonia, malnutrition, or general body wasting (inanition).Alzheimer disease can be classified as early-onset or late-onset. The signs and symptoms of the early-onset form appear before age 65, while the late-onset form appears after age 65. The early-onset form is much less common than the late-onset form, accounting for less than 5 percent of all cases of Alzheimer disease.
Last Evaluated: Sep 22, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 14:73206470
Alzheimer disease is the most common form of progressive dementia in the elderly. It is a neurodegenerative disorder characterized by the neuropathologic findings of intracellular neurofibrillary tangles (NFT) and extracellular amyloid plaques that accumulate in vulnerable brain regions (Sennvik et al., 2000). Terry and Davies (1980) pointed out that the 'presenile' form, with onset before age 65, is identical to the most common form of late-onset or 'senile' dementia, and suggested the term 'senile dementia of the Alzheimer type' (SDAT). Haines (1991) reviewed the genetics of AD. Selkoe (1996) reviewed the pathophysiology, chromosomal loci, and pathogenetic mechanisms of Alzheimer disease. Theuns and Van Broeckhoven (2000) reviewed the transcriptional regulation of the genes involved in Alzheimer disease. Genetic Heterogeneity of Alzheimer Disease Alzheimer disease is a genetically heterogeneous disorder. See also AD2 (104310), associated with the APOE*4 allele (107741) on chromosome 19; AD3 (607822), caused by mutation in the presenilin-1 gene (PSEN1; 104311) on 14q; and AD4 (606889), caused by mutation in the PSEN2 gene (600759) on 1q31. There is evidence for additional AD loci on other chromosomes; see AD5 (602096) on 12p11, AD6 (605526) on 10q24, AD7 (606187) on 10p13, AD8 (607116) on 20p, AD9 (608907), associated with variation in the ABCA7 gene (605414) on 19p13, AD10 (609636) on 7q36, AD11 (609790) on 9q22, AD12 (611073) on 8p12-q22, AD13 (611152) on 1q21, AD14 (611154) on 1q25, AD15 (611155) on 3q22-q24, AD16 (300756) on Xq21.3, AD17 (615080) on 6p21.2, and AD18 (615590), associated with variation in the ADAM10 gene (602192) on 15q21. Evidence also suggests that mitochondrial DNA polymorphisms may be risk factors in Alzheimer disease (502500). Finally, there have been associations between AD and various polymorphisms in other genes, including alpha-2-macroglobulin (A2M; 103950.0005), low density lipoprotein-related protein-1 (LRP1; 107770), the transferrin gene (TF; 190000), the hemochromatosis gene (HFE; 613609), the NOS3 gene (163729), the vascular endothelial growth factor gene (VEGF; 192240), the ABCA2 gene (600047), and the TNF gene (191160) (see MOLECULAR GENETICS).
Last Evaluated: Sep 22, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 14:73206470
Last Evaluated: Sep 22, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 14:73206470
Last Evaluated: Sep 22, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 14:73206470
Frontotemporal dementia (FTD) refers to a clinical manifestation of the pathologic finding of frontotemporal lobar degeneration (FTLD). FTD, the most common subtype of FTLD, is a behavioral variant characterized by changes in social and personal conduct with loss of volition, executive dysfunction, loss of abstract thought, and decreased speech output. A second clinical subtype of FTLD is 'semantic dementia,' characterized by specific loss of comprehension of language and impaired facial and object recognition. A third clinical subtype of FTLD is 'primary progressive aphasia' (PPA), characterized by a reduction in speech production, speech errors, and word retrieval difficulties resulting in mutism and an inability to communicate. All subtypes have relative preservation of memory, at least in the early stages. FTLD is often associated with parkinsonism or motor neuron disease (MND) resembling amyotrophic lateral sclerosis (ALS; 105400) (reviews by Tolnay and Probst, 2002 and Mackenzie and Rademakers, 2007). Mackenzie et al. (2009, 2010) provided a classification of FTLD subtypes according to the neuropathologic findings (see PATHOGENESIS below). Clinical Variability of Tauopathies Tauopathies comprise a clinically variable group of neurodegenerative diseases characterized neuropathologically by accumulation of abnormal MAPT-positive inclusions in nerve and/or glial cells. In addition to frontotemporal dementia, semantic dementia, and PPA, different clinical syndromes with overlapping features have been described, leading to confusion in the terminology (Tolnay and Probst, 2002). Other terms used historically include parkinsonism and dementia with pallidopontonigral degeneration (PPND) (Wszolek et al., 1992); disinhibition-dementia-parkinsonism-amyotrophy complex (DDPAC) (Lynch et al., 1994); frontotemporal dementia with parkinsonism (FLDEM) (Yamaoka et al., 1996); and multiple system tauopathy with presenile dementia (MSTD) (Spillantini et al., 1997). These disorders are characterized by variable degrees of frontal lobe dementia, parkinsonism, motor neuron disease, and amyotrophy. Other neurodegenerative associated with mutations in the MAPT gene include Pick disease (172700) and progressive supranuclear palsy (PSP; 601104), Inherited neurodegenerative tauopathies linked to chromosome 17 and caused by mutation in the MAPT gene have also been collectively termed 'FTDP17' (Lee et al., 2001). Kertesz (2003) suggested the term 'Pick complex' to represent the overlapping syndromes of FTD, primary progressive aphasia (PPA), corticobasal degeneration (CBD), PSP, and FTD with motor neuron disease. He noted that frontotemporal dementia may also be referred to as 'clinical Pick disease' and that the term 'Pick disease' should be restricted to the pathologic finding of Pick bodies. Genetic Heterogeneity of Frontotemporal Lobar Degeneration Mutations in several different genes can cause frontotemporal dementia and frontotemporal lobar degeneration, with or without motor neuron disease. See FTLD with TDP43 inclusions (607485), caused by mutation in the GRN gene (138945) on chromosome 17q21; FTLD mapping to chromosome 3 (600795), caused by mutation in the CHMP2B gene (609512); inclusion body myopathy with Paget disease and FTD (IBMPFD; 167320), caused by mutation in the VCP gene (601023) on chromosome 9p13; ALS6 (608030), caused by mutation in the FUS gene (137070) on 16p11; ALS10 (612069), caused by mutation in the TARDBP gene (605078) on 1p36; and FTDALS (105550), caused by mutation in the C9ORF72 gene (614260) on 9p. In 1 family with FTD, a mutation was identified in the presenilin-1 gene (PSEN1; 104311) on chromosome 14, which is usually associated with a familial form of early-onset Alzheimer disease (AD3; 607822).
Last Evaluated: Sep 22, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 14:73206470
Pick disease refers to the neuropathologic finding of 'Pick bodies,' which are argyrophilic, intraneuronal inclusions, and 'Pick cells,' which are enlarged neurons. The clinical correlates of Pick disease of brain include those of frontotemporal dementia, which encompass the behavioral variant of FTD, semantic dementia, and progressive nonfluent aphasia (summary by Piguet et al., 2011). Kertesz (2003) suggested the term 'Pick complex' to represent the overlapping syndromes of FTD, primary progressive aphasia (PPA), corticobasal degeneration (CBD), progressive supranuclear palsy (601104), and FTD with motor neuron disease. He noted that frontotemporal dementia may also be referred to as 'clinical Pick disease,' and that the term 'Pick disease' should be restricted to the pathologic finding of Pick bodies.
Last Evaluated: Sep 22, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 14:73206470
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Sep 22, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 14:73206470
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Sep 22, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 14:73206470
Benign/Likely benign
Hetero
Gene:
COL2A1
Variant:
c.1266+7G>A
rsID: rs41317915
Ref Allele: C
Alt Allele: T
Freq: 1.2997%uncommon
CADD: 6.973
ClinVar Submissions (4)
Last Evaluated: Feb 22, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:47987262
Last Evaluated: Feb 22, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:47987262
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Feb 22, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:47987262
Benign/Likely benign
Hetero
Gene:
TCTN2
Variant:
c.1612+12C>T
rsID: rs117614122
Ref Allele: C
Alt Allele: T
Freq: 1.3204%uncommon
CADD: 0.222
ClinVar Submissions (2)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 31, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 12:123699822
Benign
Hetero
Gene:
MYH3
Variant:
c.699C>T
(p.Asn233=)
rsID: rs16943604
Ref Allele: G
Alt Allele: A
Freq: 1.3204%uncommon
CADD: 7.651
ClinVar Submissions (3)
A non-progressive finding characterized by multiple joint contractures found throughout the body at birth.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:10648593
Freeman-Sheldon syndrome (FSS), or DA2A, is phenotypically similar to DA1. In addition to contractures of the hands and feet, FSS is characterized by oropharyngeal abnormalities, scoliosis, and a distinctive face that includes a very small oral orifice (often only a few millimeters in diameter at birth), puckered lips, and an H-shaped dimple of the chin; hence, FSS has been called 'whistling face syndrome.' The limb phenotypes of DA1 and FSS may be so similar that they can only be distinguished by the differences in facial morphology (summary by Bamshad et al., 2009). For a general phenotypic description and a discussion of genetic heterogeneity of distal arthrogryposis, see DA1 (108120).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:10648593
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:10648593
Benign/Likely benign
Hetero
Gene:
FREM1
Variant:
c.1394G>C
(p.Gly465Ala)
rsID: rs41298151
Ref Allele: C
Alt Allele: G
Freq: 1.3212%uncommon
CADD: 25.8
ClinVar Submissions (3)
Diaphragmatic hernia that is present at birth.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 9:14842660
Manitoba oculotrichoanal (MOTA) syndrome is characterized by an aberrant hairline (unilateral or bilateral wedge-shaped extension of the anterior hairline from the temple region to the ipsilateral eye) and anomalies of the eyes (ocular hypertelorism, anophthalmia/microphthalmia, cryptophthalmos, colobomas of the upper eyelid and corneopalpebral synechiae), nose (bifid or wide with a notched tip), abdominal wall (omphalocele or umbilical hernia), and anus (stenosis and/or anterior displacement of the anal opening). The manifestations and degree of severity vary even among affected members of the same family. Growth and psychomotor development are normal.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 9:14842660
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 9:14842660
Conflicting/Uncertain
Hetero
Gene:
SULT1C3
Variant:
c.108G>A
(p.Trp36Ter)
rsID: rs112050262
Ref Allele: G
Alt Allele: A
Freq: 1.322%uncommon
CADD: 36
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 28, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:108247302
Benign
Hetero
Gene:
FAH
Variant:
c.1021C>T
(p.Arg341Trp)
rsID: rs11555096
Ref Allele: C
Alt Allele: T
Freq: 1.3371%uncommon
CADD: 24.5
ClinVar Submissions (4)
Last Evaluated: Jul 30, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: other
Assembly: GRCh38
Chromosome/Position: 15:80180184
OMIM Allelic Variant: 613871.0006
Untreated tyrosinemia type I usually presents either in young infants with severe liver involvement or later in the first year with liver dysfunction and renal tubular dysfunction associated with growth failure and rickets. Untreated children may have repeated, often unrecognized, neurologic crises lasting one to seven days that can include change in mental status, abdominal pain, peripheral neuropathy, and/or respiratory failure requiring mechanical ventilation. Death in the untreated child usually occurs before age ten years, typically from liver failure, neurologic crisis, or hepatocellular carcinoma. Combined treatment with nitisinone and a low-tyrosine diet has resulted in a greater than 90% survival rate, normal growth, improved liver function, prevention of cirrhosis, correction of renal tubular acidosis, and improvement in secondary rickets.
Last Evaluated: Jul 30, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: other
Assembly: GRCh38
Chromosome/Position: 15:80180184
OMIM Allelic Variant: 613871.0006
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jul 30, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: other
Assembly: GRCh38
Chromosome/Position: 15:80180184
OMIM Allelic Variant: 613871.0006
Low clinical importance, Uncertain benign — This variant shows pseudodeficiency for production of FAH protein which is connected with hereditary tyrosinemia type I. Pseudodeficiency was confirmed with site-directed mutagenesis and expression in a rabbit reticulocyte lysate system. The allelic frequency in 516 Norwegian controls was 0.022.
Clinically Significant
Hetero
Gene:
SH3BP2
Variant:
c.*2510A>G
rsID: rs74805026
Ref Allele: A
Alt Allele: G
Freq: 1.3387%uncommon
CADD: 0.143
ClinVar Submissions (1)
Cherubism is a childhood-onset, autoinflammatory bone disease characterized by bilateral and symmetric proliferative fibroosseous lesions limited to the mandible and maxilla. The enlargement is usually symmetric in nature. The phenotype ranges from no clinical manifestations to severe mandibular and maxillary overgrowth with respiratory, vision, speech, and swallowing problems. In most affected persons, teeth are displaced, unerupted, unformed, or absent, or may appear to be floating in cystlike spaces; malocclusion, premature exfoliation of deciduous teeth, and root resorption have also been reported. The course and duration of the active process of bone destruction varies between affected individuals; the onset is usually in early childhood, and typically new lesions can occur until puberty. Regression of the lesions occurs as they become filled with bone and remodel during the second and third decade of life. By age 30 years, the facial abnormalities associated with cherubism are not usually recognizable and residual deformity of the jaws is rare. Typically, cherubism is an isolated benign condition; the affected person has normal intellectual skills and is without other physical anomalies.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 4:2836344
Likely benign
Hetero
Gene:
NF1
Variant:
c.168C>T
(p.Ser56=)
rsID: rs17881168
Ref Allele: C
Alt Allele: T
Freq: 1.3435%uncommon
CADD: 6.845
ClinVar Submissions (8)
Watson syndrome is an autosomal dominant disorder characterized by pulmonic stenosis, cafe-au-lait spots, decreased intellectual ability (Watson, 1967), and short stature (Partington et al., 1985). Most affected individuals have relative macrocephaly and Lisch nodules and about one-third of those affected have neurofibroma (Allanson et al., 1991).
Last Evaluated: Aug 11, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:31156090
The condition of a pattern of malignancies within a family, but not every individual's necessarily having the same neoplasm. Characteristically the tumor tends to occur at an earlier than average age, individuals may have more than one primary tumor, the tumors may be multicentric, usually more than 25 percent of the individuals in direct lineal descent from the proband are affected, and the cancer predisposition in these families behaves as an autosomal dominant trait with about 60 percent penetrance.
Last Evaluated: Aug 11, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:31156090
Spinal neurofibromatosis is an autosomal dominant disorder characterized by a high load of spinal tumors. These tumors may be asymptomatic or result in neurologic symptoms, including back pain, difficulty walking, and paresthesias. Spinal NF is considered to be a subtype of neurofibromatosis type I (NF1; 162200), which is an allelic disorder. Patients with spinal NF may or may not have the classic cutaneous cafe-au-lait pigmentary macules or ocular Lisch nodules typically observed in patients with classic NF1. Patients with spinal NF should be followed closely for spinal sequelae (summary by Burkitt Wright et al., 2013).
Last Evaluated: Aug 11, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:31156090
Neurofibromatosis 1 (NF1) is characterized by multiple café au lait spots, axillary and inguinal freckling, multiple cutaneous neurofibromas, iris Lisch nodules, and choroidal freckling. About half of people with NF1 have plexiform neurofibromas, but most are internal and not suspected clinically. Learning disabilities are present in at least 50% of individuals with NF1. Less common but potentially more serious manifestations include optic nerve and other central nervous system gliomas, malignant peripheral nerve sheath tumors, scoliosis, tibial dysplasia, and vasculopathy.
Last Evaluated: Aug 11, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:31156090
A variant of neurofibromatosis type 1 characterised by the combination of features of neurofibromatosis type 1, such as café-au-lait spots, iris Lisch nodules, axillary and inguinal freckling, optic nerve glioma and multiple neurofibromas; and Noonan syndrome, with features such as short stature, typical facial features, congenital heart defects and unusual pectus deformity.
Last Evaluated: Aug 11, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:31156090
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Aug 11, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:31156090
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 11, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:31156090
Benign/Likely benign
Hetero
Gene:
MOCS1
Variant:
c.*1904A>C
rsID: rs60326448
Ref Allele: T
Alt Allele: G
Freq: 1.3722%uncommon
CADD: 0.087
ClinVar Submissions (1)
Molybdenum cofactor deficiency (MOCOD) is a rare autosomal recessive metabolic disorder characterized by onset in infancy of poor feeding, intractable seizures, and severe psychomotor retardation. Characteristic biochemical abnormalities include decreased serum uric acid and increased urine sulfite levels due to the combined enzymatic deficiency of xanthine dehydrogenase (XDH; 607633) and sulfite oxidase (SUOX; 606887), both of which use molybdenum as a cofactor. Most affected individuals die in early childhood (summary by Reiss, 2000; Reiss et al., 2011). Genetic Heterogeneity of Molybdenum Cofactor Deficiency See also MOCOD, complementation group B (MOCODB; 252160), caused by mutation in the MOCS2 gene (602708) on chromosome 5q11; and MOCOD, complementation group C (MOCODC; 615501), caused by mutation in the GPHN gene (603930) on chromosome 14q24.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 6:39905221
Likely benign
Hetero
Gene:
TBXAS1
Variant:
c.1349C>A
(p.Thr450Asn)
rsID: rs5763
Ref Allele: C
Alt Allele: A
Freq: 1.3769%uncommon
CADD: 5.639
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: May 03, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:140015845
Likely benign
Hetero
Gene:
ORC1
Variant:
c.1115C>T
(p.Ala372Val)
rsID: rs3087476
Ref Allele: G
Alt Allele: A
Freq: 1.3985%uncommon
CADD: 8.253
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 06, 2015
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:52389289
Benign
Hetero
Gene:
TTN
Variant:
c.22204C>T
(p.Arg7402Cys)
rsID: rs72648987
Ref Allele: G
Alt Allele: A
Freq: 1.4144%uncommon
CADD: 17.5
ClinVar Submissions (8)
Last Evaluated: Aug 09, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 8
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:178715250
Last Evaluated: Aug 09, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 8
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:178715250
Last Evaluated: Aug 09, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 8
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:178715250
Udd distal myopathy is characterized by weakness of ankle dorsiflexion and inability to walk on the heels after age 35 years. Disease progression is slow and muscle weakness remains confined to the anterior tibial muscles. The long toe extensors become clinically involved after ten to 20 years, leading to foot drop and clumsiness when walking. In the mildest form, Udd distal myopathy can remain unnoticed even in the elderly.
Last Evaluated: Aug 09, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 8
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:178715250
Hereditary myopathy with early respiratory failure (HMERF) is a slowly progressive myopathy that typically begins in the third to fifth decades of life. The usual presenting findings are gait disturbance relating to distal leg weakness or nocturnal respiratory symptoms due to respiratory muscle weakness. Weakness eventually generalizes and affects both proximal and distal muscles. Most affected individuals require walking aids within a few years of onset; some progress to wheelchair dependence and require nocturnal noninvasive ventilatory support. The disease course varies even among individuals within the same family: some remain ambulant until their 70s whereas others may require ventilator support in their 40s.
Last Evaluated: Aug 09, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 8
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:178715250
A condition in which the myocardium is hypertrophied without an obvious cause. The hypertrophy is generally asymmetric and may be associated with obstruction of the ventricular outflow tract.
Last Evaluated: Aug 09, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 8
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:178715250
Last Evaluated: Aug 09, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 8
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:178715250
Limb-girdle muscular dystrophy is a term for a group of diseases that cause weakness and wasting of the muscles in the arms and legs. The muscles most affected are those closest to the body (proximal muscles), specifically the muscles of the shoulders, upper arms, pelvic area, and thighs.The severity, age of onset, and features of limb-girdle muscle dystrophy vary among the many subtypes of this condition and may be inconsistent even within the same family. Signs and symptoms may first appear at any age and generally worsen with time, although in some cases they remain mild.In the early stages of limb-girdle muscular dystrophy, affected individuals may have an unusual walking gait, such as waddling or walking on the balls of their feet, and may also have difficulty running. They may need to use their arms to press themselves up from a squatting position because of their weak thigh muscles. As the condition progresses, people with limb-girdle muscular dystrophy may eventually require wheelchair assistance.Muscle wasting may cause changes in posture or in the appearance of the shoulder, back, and arm. In particular, weak shoulder muscles tend to make the shoulder blades (scapulae) "stick out" from the back, a sign known as scapular winging. Affected individuals may also have an abnormally curved lower back (lordosis) or a spine that curves to the side (scoliosis). Some develop joint stiffness (contractures) that can restrict movement in their hips, knees, ankles, or elbows. Overgrowth (hypertrophy) of the calf muscles occurs in some people with limb-girdle muscular dystrophy.Weakening of the heart muscle (cardiomyopathy) occurs in some forms of limb-girdle muscular dystrophy. Some affected individuals experience mild to severe breathing problems related to the weakness of muscles needed for breathing. In some cases, the breathing problems are severe enough that affected individuals need to use a machine to help them breathe (mechanical ventilation).Intelligence is generally unaffected in limb-girdle muscular dystrophy; however, developmental delay and intellectual disability have been reported in rare forms of the disorder.
Last Evaluated: Aug 09, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 8
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:178715250
Salih myopathy is characterized by muscle weakness (manifest during the neonatal period or in early infancy) and delayed motor development; children acquire independent walking between age 20 months and four years. In the first decade of life, global motor performances are stable or tend to improve. Moderate joint and neck contractures and spinal rigidity may start in the first decade but become more obvious in the second decade. Scoliosis develops after age 11 years. Cardiac dysfunction starts between ages five and 16 years, progresses rapidly, and leads to death between ages eight and 20 years, usually from heart rhythm disturbances.
Last Evaluated: Aug 09, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 8
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:178715250
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 09, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 8
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 2:178715250
Conflicting/Uncertain
Hetero
Gene:
LIMS2
Variant:
c.875-8C>G
rsID: rs115961120
Ref Allele: G
Alt Allele: C
Freq: 1.4207%uncommon
CADD: 12.77
ClinVar Submissions (2)
Autosomal recessive muscular dystrophy with cardiomyopathy and triangular tongue (MDRCMTT) is an autosomal recessive muscle disorder characterized by onset of severe and progressive muscle weakness and atrophy in childhood, resulting in loss of independent ambulation. Patients may also have dilated cardiomyopathy and have macroglossia with a small tip, resulting in a triangular appearance of the tongue (summary by Warman Chardon et al., 2015).
Last Evaluated: Jul 21, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:127640153
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 21, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:127640153
Benign
Hetero
Gene:
ACADSB
Variant:
c.*109G>A
rsID: rs34955007
Ref Allele: G
Alt Allele: A
Freq: 1.4223%uncommon
CADD: 0.69
ClinVar Submissions (1)
2-Methylbutyryl-CoA dehydrogenase (MBD) deficiency is an autosomal recessive metabolic disorder of impaired isoleucine degradation. It is most often ascertained via newborn screening and is usually clinically asymptomatic, although some patients have been reported to have delayed development and neurologic signs. Therefore, the clinical relevance of the deficiency is unclear (Sass et al.., 2008).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 10:123053874
Conflicting/Uncertain
Hetero
Gene:
PYGL
Variant:
c.1828-21G>A
rsID: rs75220125
Ref Allele: C
Alt Allele: T
Freq: 1.4558%uncommon
CADD: 0.175
ClinVar Submissions (2)
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Apr 17, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 14:50911892
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Apr 17, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 14:50911892
Likely benign
Hetero
Gene:
ELP1
Variant:
c.2587+14C>T
rsID: rs141670242
Ref Allele: G
Alt Allele: A
Freq: 1.4765%uncommon
CADD: 2.451
ClinVar Submissions (3)
Familial dysautonomia (FD) affects the development and survival of sensory, sympathetic, and parasympathetic neurons. It is a debilitating disease present from birth. Neuronal degeneration progresses throughout life. Affected individuals have gastrointestinal dysfunction, vomiting crises, recurrent pneumonia, altered sensitivity to pain and temperature perception, and cardiovascular instability. About 40% of individuals have autonomic crises. Hypotonia contributes to delay in acquisition of motor milestones. Older individuals often have a broad-based and ataxic gait that deteriorates over time. Life expectancy is decreased.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 9:108896939
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 9:108896939
Conflicting/Uncertain
Hetero
Gene:
BRCA1
Variant:
c.5467+658G>A
rsID: rs8176313
Ref Allele: C
Alt Allele: T
Freq: 1.4797%uncommon
CADD: 8.025
ClinVar Submissions (1)
BRCA1- and BRCA2-associated hereditary breast and ovarian cancer syndrome (HBOC) is characterized by an increased risk for female and male breast cancer, ovarian cancer (includes fallopian tube and primary peritoneal cancers), and to a lesser extent other cancers such as prostate cancer, pancreatic cancer, and melanoma primarily in individuals with a BRCA2 pathogenic variant. The exact cancer risks differ slightly depending on whether HBOC is caused by a BRCA1 or BRCA2 pathogenic variant.
Last Evaluated: Jan 12, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 17:43046985
Expert Reviewed Benign
Homo
Gene:
PNPLA2
Variant:
c.793C>T
(p.Pro265Ser)
rsID: rs56152088
Ref Allele: C
Alt Allele: T
Freq: 1.4868%uncommon
CADD: 13.61
ClinVar Submissions (4)
Neutral lipid storage disease with myopathy is an autosomal recessive muscle disorder characterized by adult onset of slowly progressive proximal muscle weakness affecting the upper and lower limbs and associated with increased serum creatine kinase; distal muscle weakness may also occur. About half of patients develop cardiomyopathy later in the disease course. Other variable features include diabetes mellitus, hepatic steatosis, hypertriglyceridemia, and possibly sensorineural hearing loss. Leukocytes and muscle cells show cytoplasmic accumulation of triglycerides (summary by Reilich et al., 2011). Neutral lipid storage disease with myopathy belongs to a group of disorders termed neutral lipid storage disorders (NLSDs). These disorders are characterized by the presence of triglyceride-containing cytoplasmic droplets in leukocytes and in other tissues, including bone marrow, skin, and muscle. Chanarin-Dorfman syndrome (CDS; 275630) is defined as NLSD with ichthyosis (NLSDI). Patients with NLSDM present with myopathy but without ichthyosis (summary by Fischer et al., 2007).
Last Evaluated: Aug 03, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:823729
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 03, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:823729
Benign/Likely benign
Hetero
Gene:
ELP1
Variant:
c.751A>G
(p.Ser251Gly)
rsID: rs17853166
Ref Allele: T
Alt Allele: C
Freq: 1.4932%uncommon
CADD: 23.9
ClinVar Submissions (4)
Familial dysautonomia (FD) affects the development and survival of sensory, sympathetic, and parasympathetic neurons. It is a debilitating disease present from birth. Neuronal degeneration progresses throughout life. Affected individuals have gastrointestinal dysfunction, vomiting crises, recurrent pneumonia, altered sensitivity to pain and temperature perception, and cardiovascular instability. About 40% of individuals have autonomic crises. Hypotonia contributes to delay in acquisition of motor milestones. Older individuals often have a broad-based and ataxic gait that deteriorates over time. Life expectancy is decreased.
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 9:108917660
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 9:108917660
Conflicting/Uncertain
Hetero
Gene:
PRKG1
Variant:
c.408G>A
(p.Pro136=)
rsID: rs55806342
Ref Allele: G
Alt Allele: A
Freq: 1.506%uncommon
CADD: 0.855
ClinVar Submissions (4)
Last Evaluated: Aug 04, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 10:51153260
Last Evaluated: Aug 04, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 10:51153260
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Aug 04, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 10:51153260
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 04, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 10:51153260
Benign
Hetero
Gene:
SLC2A9
Variant:
c.841G>C
(p.Asp281His)
rsID: rs73225891
Ref Allele: C
Alt Allele: G
Freq: 1.5322%uncommon
CADD: 21.2
ClinVar Submissions (1)
Renal hypouricemia is characterized by impaired uric acid reabsorption at the apical membrane of proximal renal tubule cells. The syndrome is not lethal and may be asymptomatic. However, it is accompanied by nephrolithiasis and exercise-induced acute renal failure in about 10% of patients (Ichida et al., 2008). Genetic Heterogeneity of Renal Hypouricemia See also RHUC2 (612076), which is caused by mutation in the SLC2A9 gene (606142).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 4:9920546
Benign
Hetero
Gene:
KANSL1;MAPT
Variant:
c.*2167G>A
rsID: rs16940802
Ref Allele: G
Alt Allele: A
Freq: 1.541%uncommon
CADD: 0.483
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 17:46026338
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 17:46026338
Likely benign
Hetero
Gene:
TUBB4A
Variant:
c.1287G>A
(p.Thr429=)
rsID: rs61731566
Ref Allele: C
Alt Allele: T
Freq: 1.5458%uncommon
CADD: 0.005
ClinVar Submissions (3)
An abnormally increased muscular tone that causes fixed abnormal postures. There is a slow, intermittent twisting motion that leads to exaggerated turning and posture of the extremities and trunk.
Last Evaluated: Jun 12, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 19:6495212
TUBB4A-related leukodystrophy comprises a phenotypic spectrum in which the MRI findings range from hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) at the severe end to isolated hypomyelination at the mild end. Progressive neurologic findings reflect involvement of the pyramidal tracts (spasticity, brisk deep tendon reflexes, and Babinski sign), extrapyramidal system (rigidity, dystonia, choreoathetosis, oculogyric crisis, and perioral dyskinesia), cerebellum (ataxia, intention tremor, dysmetria), and bulbar function (dysarthria, dysphonia, and swallowing). Cognition is variably affected, usually less severely than motor function. Typically, those with H-ABC present in early childhood (ages one to three years) and those with isolated hypomyelination in later childhood or adulthood. The rate of progression varies with disease severity.
Last Evaluated: Jun 12, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 19:6495212
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 12, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 19:6495212
Benign/Likely benign
Hetero
Gene:
FREM2
Variant:
c.*1694A>G
rsID: rs17443589
Ref Allele: A
Alt Allele: G
Freq: 1.5561%uncommon
CADD: 0.933
ClinVar Submissions (1)
Fraser syndrome is an autosomal recessive malformation disorder characterized by cryptophthalmos, syndactyly, and abnormalities of the respiratory and urogenital tract (summary by van Haelst et al., 2008). Genetic Heterogeneity of Fraser Syndrome Fraser syndrome-2 (FRASRS2) is caused by mutation in the FREM2 gene (608945) on chromosome 13q13, and Fraser syndrome-3 (FRASRS3) is caused by mutation in the GRIP1 gene (604597) on chromosome 12q14. See Bowen syndrome (211200) for a comparable but probably distinct syndrome of multiple congenital malformations.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 13:38882481
Conflicting/Uncertain
Hetero
Gene:
PRKAR1A
Variant:
c.*1837G>T
rsID: rs201999343
Ref Allele: G
Alt Allele: T
Freq: 1.5657%uncommon
CADD: 19.05
ClinVar Submissions (1)
A syndrome of short hands and feet, nasal hypoplasia, mental retardation, and characteristic facies.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 17:68532286
Carney complex (CNC) is characterized by skin pigmentary abnormalities, myxomas, endocrine tumors or overactivity, and schwannomas. Pale brown to black lentigines are the most common presenting feature of CNC and typically increase in number at puberty. Cardiac myxomas occur at a young age, may occur in any or all cardiac chambers, and can manifest as intracardiac obstruction of blood flow, embolic phenomenon, and/or heart failure. Other sites for myxomas include the skin, breast, oropharynx, and female genital tract. Primary pigmented nodular adrenocortical disease (PPNAD), which causes Cushing syndrome, is the most frequently observed endocrine tumor in CNC, occurring in approximately 25% of affected individuals. Large-cell calcifying Sertoli cell tumors (LCCSCTs) are observed in one third of affected males within the first decade and in most adult males. Up to 75% of individuals with CNC have multiple thyroid nodules, most of which are nonfunctioning thyroid follicular adenomas. Clinically evident acromegaly from a growth hormone (GH)-producing adenoma is evident in approximately 10% of adults. Psammomatous melanotic schwannoma (PMS), a rare tumor of the nerve sheath, occurs in an estimated 10% of affected individuals. The median age of diagnosis is 20 years.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 17:68532286
Likely benign
Hetero
Gene:
DMD
Variant:
c.832-17C>A
rsID: rs72470514
Ref Allele: G
Alt Allele: T
Freq: 1.5816%uncommon
ClinVar Submissions (2)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: May 09, 2014
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: X:32698015
Benign
Homo
Gene:
DMD
Variant:
c.832-18C>G
rsID: rs72470515
Ref Allele: G
Alt Allele: C
Freq: 1.5816%uncommon
ClinVar Submissions (2)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: May 09, 2014
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: X:32698016
Benign
Homo
Gene:
ALDH6A1
Variant:
c.*142C>T
rsID: rs8017248
Ref Allele: G
Alt Allele: A
Freq: 1.6039%uncommon
CADD: 8.186
ClinVar Submissions (1)
Methylmalonate semialdehyde dehydrogenase deficiency is a rare autosomal recessive inborn error of metabolism with a highly variable phenotype. Some patients may be asymptomatic, whereas others show global developmental delay, nonspecific dysmorphic features, and delayed myelination on brain imaging. Laboratory studies typically show increased urinary 3-hydroxyisobutyric acid, although additional metabolic abnormalities may also be observed (summary by Marcadier et al., 2013).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 14:74060500
Benign
Hetero
Gene:
MYH3
Variant:
c.4128C>T
(p.Tyr1376=)
rsID: rs112569418
Ref Allele: G
Alt Allele: A
Freq: 1.6151%uncommon
CADD: 6.831
ClinVar Submissions (3)
A non-progressive finding characterized by multiple joint contractures found throughout the body at birth.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:10635411
Freeman-Sheldon syndrome (FSS), or DA2A, is phenotypically similar to DA1. In addition to contractures of the hands and feet, FSS is characterized by oropharyngeal abnormalities, scoliosis, and a distinctive face that includes a very small oral orifice (often only a few millimeters in diameter at birth), puckered lips, and an H-shaped dimple of the chin; hence, FSS has been called 'whistling face syndrome.' The limb phenotypes of DA1 and FSS may be so similar that they can only be distinguished by the differences in facial morphology (summary by Bamshad et al., 2009). For a general phenotypic description and a discussion of genetic heterogeneity of distal arthrogryposis, see DA1 (108120).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:10635411
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:10635411
Benign/Likely benign
Hetero
Gene:
TNXB
Variant:
c.1734C>T
(p.Asp578=)
rsID: rs41270458
Ref Allele: G
Alt Allele: A
Freq: 1.6413%uncommon
CADD: 0.802
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 6:32096119
Benign
Hetero
Gene:
ROBO2
Variant:
c.547-3C>T
rsID: rs113680429
Ref Allele: C
Alt Allele: T
Freq: 1.6477%uncommon
CADD: 8.587
ClinVar Submissions (1)
Abnormal (retrograde) movement of urine from the bladder into ureters or kidneys related to inadequacy of the valvular mechanism at the ureterovesicular junction or other causes.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 3:77481096
Likely benign
Hetero
Gene:
MYO7A
Variant:
c.5619G>A
(p.Arg1873=)
rsID: rs45450893
Ref Allele: G
Alt Allele: A
Freq: 1.6557%uncommon
CADD: 17.66
ClinVar Submissions (3)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:77205600
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:77205600
Usher syndrome is a condition characterized by partial or total hearing loss and vision loss that worsens over time. The hearing loss is classified as sensorineural, which means that it is caused by abnormalities of the inner ear. The loss of vision is caused by an eye disease called retinitis pigmentosa (RP), which affects the layer of light-sensitive tissue at the back of the eye (the retina). Vision loss occurs as the light-sensing cells of the retina gradually deteriorate. Night vision loss begins first, followed by blind spots that develop in the side (peripheral) vision. Over time, these blind spots enlarge and merge to produce tunnel vision. In some cases, vision is further impaired by clouding of the lens of the eye (cataracts). However, many people with retinitis pigmentosa retain some central vision throughout their lives.Researchers have identified three major types of Usher syndrome, designated as types I, II, and III. These types are distinguished by the severity of hearing loss, the presence or absence of balance problems, and the age at which signs and symptoms appear. The types are further divided into subtypes based on their genetic cause.Most individuals with Usher syndrome type I are born with severe to profound hearing loss. Progressive vision loss caused by retinitis pigmentosa becomes apparent in childhood. This type of Usher syndrome also causes abnormalities of the vestibular system, which is the part of the inner ear that helps maintain the body's balance and orientation in space. As a result of the vestibular abnormalities, children with the condition have trouble with balance. They begin sitting independently and walking later than usual, and they may have difficulty riding a bicycle and playing certain sports.Usher syndrome type II is characterized by hearing loss from birth and progressive vision loss that begins in adolescence or adulthood. The hearing loss associated with this form of Usher syndrome ranges from mild to severe and mainly affects the ability to hear high-frequency sounds. For example, it is difficult for affected individuals to hear high, soft speech sounds, such as those of the letters d and t. The degree of hearing loss varies within and among families with this condition, and it may become more severe over time. Unlike the other forms of Usher syndrome, type II is not associated with vestibular abnormalities that cause difficulties with balance.People with Usher syndrome type III experience hearing loss and vision loss beginning somewhat later in life. Unlike the other forms of Usher syndrome, type III is usually associated with normal hearing at birth. Hearing loss typically begins during late childhood or adolescence, after the development of speech, and becomes more severe over time. By middle age, most affected individuals have profound hearing loss. Vision loss caused by retinitis pigmentosa also develops in late childhood or adolescence. Some people with Usher syndrome type III develop vestibular abnormalities that cause problems with balance.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:77205600
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:77205600
Benign/Likely benign
Hetero
Gene:
NEUROD1
Variant:
c.590C>A
(p.Pro197His)
rsID: rs8192556
Ref Allele: G
Alt Allele: T
Freq: 1.6581%uncommon
CADD: 23.4
ClinVar Submissions (4)
Maturity-onset diabetes of the young is an autosomal dominant form of diabetes typically occurring before 25 years of age and caused by primary insulin secretion defects. Despite its low prevalence, MODY is not a single entity but represents genetic, metabolic, and clinical heterogeneity (Vaxillaire and Froguel, 2008). Genetic Heterogeneity of MODY MODY1 (125850) is caused by heterozygous mutation in the hepatocyte nuclear factor-4-alpha gene (HNF4A; 600281) on chromosome 20. MODY2 (125851) is caused by heterozygous mutation in the glucokinase gene (GCK; 138079) on chromosome 7. MODY3 (600496) is caused by heterozygous mutation in the hepatocyte nuclear factor-1alpha gene (HNF1A; 142410) on chromosome 12q24.2. MODY4 (606392) is caused by heterozygous mutation in the pancreas/duodenum homeobox protein-1 gene (PDX1; 600733) on chromosome 13q12.1. MODY5 (137920) is caused by heterozygous mutation in the gene encoding hepatic transcription factor-2 (TCF2; 189907) on chromosome 17cen-q21.3. MODY6 (606394) is caused by heterozygous mutation in the NEUROD1 gene (601724) on chromosome 2q32. MODY7 (610508) is caused by heterozygous mutation in the KLF11 gene (603301) on chromosome 2p25. MODY8 (609812), or diabetes-pancreatic exocrine dysfunction syndrome, is caused by heterozygous mutation in the CEL gene (114840) on chromosome 9q34. MODY9 (612225) is caused by heterozygous mutation in the PAX4 gene (167413) on chromosome 7q32. MODY10 (613370) is caused by heterozygous mutation in the insulin gene (INS; 176730) on chromosome 11p15.5. MODY11 (613375) is caused by heterozygous mutation in the BLK gene (191305) on chromosome 8p23. MODY13 (616329) is caused by heterozygous mutation in the KCNJ11 gene (600937) on chromosome 11p15. MODY14 (616511) is caused by heterozygous mutation in the APPL1 gene (604299) on chromosome 3p14.
Last Evaluated: Oct 06, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:181678271
Diabetes mellitus caused by mutation(s) in a single gene, usually presenting in childhood or early adulthood.
Last Evaluated: Oct 06, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:181678271
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Oct 06, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:181678271
Low clinical importance, Uncertain benign — Tentatively presumed benign. Other disruptive mutations in this gene have been reported to cause type 2 diabetes in a dominant manner, but this was found in a PGP participant who does not report having the disease.
Benign/Likely benign
Hetero
Gene:
TTN
Variant:
c.26080A>T
(p.Thr8694Ser)
rsID: rs72650006
Ref Allele: T
Alt Allele: A
Freq: 1.6621%uncommon
CADD: 22.7
ClinVar Submissions (8)
Last Evaluated: Aug 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:178704660
Last Evaluated: Aug 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:178704660
Last Evaluated: Aug 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:178704660
Udd distal myopathy is characterized by weakness of ankle dorsiflexion and inability to walk on the heels after age 35 years. Disease progression is slow and muscle weakness remains confined to the anterior tibial muscles. The long toe extensors become clinically involved after ten to 20 years, leading to foot drop and clumsiness when walking. In the mildest form, Udd distal myopathy can remain unnoticed even in the elderly.
Last Evaluated: Aug 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:178704660
Hereditary myopathy with early respiratory failure (HMERF) is a slowly progressive myopathy that typically begins in the third to fifth decades of life. The usual presenting findings are gait disturbance relating to distal leg weakness or nocturnal respiratory symptoms due to respiratory muscle weakness. Weakness eventually generalizes and affects both proximal and distal muscles. Most affected individuals require walking aids within a few years of onset; some progress to wheelchair dependence and require nocturnal noninvasive ventilatory support. The disease course varies even among individuals within the same family: some remain ambulant until their 70s whereas others may require ventilator support in their 40s.
Last Evaluated: Aug 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:178704660
A condition in which the myocardium is hypertrophied without an obvious cause. The hypertrophy is generally asymmetric and may be associated with obstruction of the ventricular outflow tract.
Last Evaluated: Aug 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:178704660
Last Evaluated: Aug 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:178704660
Limb-girdle muscular dystrophy is a term for a group of diseases that cause weakness and wasting of the muscles in the arms and legs. The muscles most affected are those closest to the body (proximal muscles), specifically the muscles of the shoulders, upper arms, pelvic area, and thighs.The severity, age of onset, and features of limb-girdle muscle dystrophy vary among the many subtypes of this condition and may be inconsistent even within the same family. Signs and symptoms may first appear at any age and generally worsen with time, although in some cases they remain mild.In the early stages of limb-girdle muscular dystrophy, affected individuals may have an unusual walking gait, such as waddling or walking on the balls of their feet, and may also have difficulty running. They may need to use their arms to press themselves up from a squatting position because of their weak thigh muscles. As the condition progresses, people with limb-girdle muscular dystrophy may eventually require wheelchair assistance.Muscle wasting may cause changes in posture or in the appearance of the shoulder, back, and arm. In particular, weak shoulder muscles tend to make the shoulder blades (scapulae) "stick out" from the back, a sign known as scapular winging. Affected individuals may also have an abnormally curved lower back (lordosis) or a spine that curves to the side (scoliosis). Some develop joint stiffness (contractures) that can restrict movement in their hips, knees, ankles, or elbows. Overgrowth (hypertrophy) of the calf muscles occurs in some people with limb-girdle muscular dystrophy.Weakening of the heart muscle (cardiomyopathy) occurs in some forms of limb-girdle muscular dystrophy. Some affected individuals experience mild to severe breathing problems related to the weakness of muscles needed for breathing. In some cases, the breathing problems are severe enough that affected individuals need to use a machine to help them breathe (mechanical ventilation).Intelligence is generally unaffected in limb-girdle muscular dystrophy; however, developmental delay and intellectual disability have been reported in rare forms of the disorder.
Last Evaluated: Aug 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:178704660
Salih myopathy is characterized by muscle weakness (manifest during the neonatal period or in early infancy) and delayed motor development; children acquire independent walking between age 20 months and four years. In the first decade of life, global motor performances are stable or tend to improve. Moderate joint and neck contractures and spinal rigidity may start in the first decade but become more obvious in the second decade. Scoliosis develops after age 11 years. Cardiac dysfunction starts between ages five and 16 years, progresses rapidly, and leads to death between ages eight and 20 years, usually from heart rhythm disturbances.
Last Evaluated: Aug 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:178704660
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:178704660
Benign/Likely benign
Hetero
Gene:
FGFR3
Variant:
c.1075+5C>T
rsID: rs3135885
Ref Allele: C
Alt Allele: T
Freq: 1.6692%uncommon
CADD: 6.673
ClinVar Submissions (3)
Last Evaluated: Jun 14, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 4:1803841
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 4:1803841
Benign
Hetero
Gene:
TRDN
Variant:
c.1620A>G
(p.Ile540Met)
rsID: rs7771303
Ref Allele: T
Alt Allele: C
Freq: 1.6692%uncommon
CADD: 0.111
ClinVar Submissions (6)
Last Evaluated: Jun 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:123273341
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is characterized by episodic syncope occurring during exercise or acute emotion in individuals without structural cardiac abnormalities. The underlying cause of these episodes is the onset of fast ventricular tachycardia (bidirectional or polymorphic). Spontaneous recovery may occur when these arrhythmias self-terminate. In other instances, ventricular tachycardia may degenerate into ventricular fibrillation and cause sudden death if cardiopulmonary resuscitation is not readily available. The mean age of onset of symptoms (usually a syncopal episode) is between age seven and twelve years; onset as late as the fourth decade of life has been reported. If untreated, CPVT is highly lethal, as approximately 30% of affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. Sudden death may be the first manifestation of the disease.
Last Evaluated: Jun 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:123273341
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:123273341
Benign/Likely benign
Hetero
Gene:
ELP1
Variant:
c.189C>T
(p.Leu63=)
rsID: rs2230786
Ref Allele: G
Alt Allele: A
Freq: 1.7035%uncommon
CADD: 16.1
ClinVar Submissions (3)
Familial dysautonomia (FD) affects the development and survival of sensory, sympathetic, and parasympathetic neurons. It is a debilitating disease present from birth. Neuronal degeneration progresses throughout life. Affected individuals have gastrointestinal dysfunction, vomiting crises, recurrent pneumonia, altered sensitivity to pain and temperature perception, and cardiovascular instability. About 40% of individuals have autonomic crises. Hypotonia contributes to delay in acquisition of motor milestones. Older individuals often have a broad-based and ataxic gait that deteriorates over time. Life expectancy is decreased.
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 9:108929883
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 9:108929883
Conflicting/Uncertain
Hetero
Gene:
ACADM
Variant:
c.31-73T>C
rsID: rs142795930
Ref Allele: T
Alt Allele: C
Freq: 1.7345%uncommon
CADD: 0.238
ClinVar Submissions (1)
Medium-chain acyl-coenzyme A dehydrogenase (MCAD) is one of the enzymes involved in mitochondrial fatty acid ß-oxidation, which fuels hepatic ketogenesis, a major source of energy once hepatic glycogen stores become depleted during prolonged fasting and periods of higher energy demands. In a typical clinical scenario, a previously healthy child with MCAD deficiency presents with hypoketotic hypoglycemia, vomiting, and lethargy triggered by a common illness. Seizures may occur. Hepatomegaly and liver disease are often present during an acute episode, which can quickly progress to coma and death. Children are normal at birth and – if not identified through newborn screening – typically present between ages three and 24 months; later presentation, even into adulthood, is possible. The prognosis is excellent once the diagnosis is established and frequent feedings are instituted to avoid any prolonged period of fasting.
Last Evaluated: Feb 20, 2015
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:75728328
Benign
Hetero
Gene:
FGFR3
Variant:
c.348C>T
(p.Arg116=)
rsID: rs2305179
Ref Allele: C
Alt Allele: T
Freq: 1.7512%uncommon
CADD: 0.038
ClinVar Submissions (4)
Last Evaluated: Jun 14, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 4:1799492
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 4:1799492
Benign
Hetero
Gene:
TIMM44
Variant:
c.396C>T
(p.Ser132=)
rsID: rs55715900
Ref Allele: G
Alt Allele: A
Freq: 1.7592%uncommon
CADD: 14.41
ClinVar Submissions (2)
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Feb 23, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 19:7934236
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Feb 23, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 19:7934236
Benign
Hetero
Gene:
ELP1
Variant:
c.959-15C>T
rsID: rs112114410
Ref Allele: G
Alt Allele: A
Freq: 1.7616%uncommon
CADD: 4.497
ClinVar Submissions (3)
Familial dysautonomia (FD) affects the development and survival of sensory, sympathetic, and parasympathetic neurons. It is a debilitating disease present from birth. Neuronal degeneration progresses throughout life. Affected individuals have gastrointestinal dysfunction, vomiting crises, recurrent pneumonia, altered sensitivity to pain and temperature perception, and cardiovascular instability. About 40% of individuals have autonomic crises. Hypotonia contributes to delay in acquisition of motor milestones. Older individuals often have a broad-based and ataxic gait that deteriorates over time. Life expectancy is decreased.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 9:108912509
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 9:108912509
Conflicting/Uncertain
Hetero
Gene:
BRCA2
Variant:
c.8754+249G>A
rsID: rs11571760
Ref Allele: G
Alt Allele: A
Freq: 1.7672%uncommon
CADD: 0.697
ClinVar Submissions (1)
BRCA1- and BRCA2-associated hereditary breast and ovarian cancer syndrome (HBOC) is characterized by an increased risk for female and male breast cancer, ovarian cancer (includes fallopian tube and primary peritoneal cancers), and to a lesser extent other cancers such as prostate cancer, pancreatic cancer, and melanoma primarily in individuals with a BRCA2 pathogenic variant. The exact cancer risks differ slightly depending on whether HBOC is caused by a BRCA1 or BRCA2 pathogenic variant.
Last Evaluated: Jan 12, 2015
Review Status: reviewed by expert panel
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 13:32377040
Expert Reviewed Benign
Hetero
Gene:
PPP1R3A
Variant:
c.2649G>T
(p.Arg883Ser)
rsID: rs1800000
Ref Allele: C
Alt Allele: A
Freq: 1.7688%uncommon
CADD: 0.007
ClinVar Submissions (1)
Diabetes mellitus caused by mutation(s) in a single gene, usually presenting in childhood or early adulthood.
Last Evaluated: Apr 07, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 7:113878443
Benign
Hetero
Gene:
SCNN1A
Variant:
c.*633G>T
rsID: rs62618735
Ref Allele: C
Alt Allele: A
Freq: 1.7863%uncommon
CADD: 0.577
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 12:6347240
Autosomal recessive pseudohypoaldosteronism type I is characterized by renal salt wasting and high concentrations of sodium in sweat, stool, and saliva. The disorder involves multiple organ systems and is especially threatening in the neonatal period. Laboratory evaluation shows hyponatremia, hyperkalemia, and increased plasma renin activity with high serum aldosterone concentrations. Respiratory tract infections are common in affected children and may be mistaken for cystic fibrosis (CF; 219700). Aggressive salt replacement and control of hyperkalemia results in survival, and the disorder appears to become less severe with age (review by Scheinman et al., 1999). A milder, autosomal dominant form of type I pseudohypoaldosteronism (PHA1A; 177735) is caused by mutations in the mineralocorticoid receptor gene (MCR, NR3C2; 600983). Gitelman syndrome (263800), another example of primary renal tubular salt wasting, is due to mutation in the thiazide-sensitive sodium-chloride cotransporter (SLC12A3; 600968). Hanukoglu and Hanukoglu (2016) provided a detailed review of the ENaC gene family, including structure, function, tissue distribution, and associated inherited diseases.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 12:6347240
Likely benign
Hetero
Gene:
MYO1C
Variant:
c.2697G>A
(p.Lys899=)
rsID: rs45598333
Ref Allele: C
Alt Allele: T
Freq: 1.7927%uncommon
CADD: 13.36
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Feb 27, 2018
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 17:1468082
Likely benign
Hetero
Gene:
C12orf65
Variant:
c.44G>A
(p.Arg15Gln)
rsID: rs78651634
Ref Allele: G
Alt Allele: A
Freq: 1.8046%uncommon
CADD: 13.71
ClinVar Submissions (5)
Last Evaluated: Aug 02, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 12:123253718
Spasticity and weakness of the leg and hip muscles.
Last Evaluated: Aug 02, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 12:123253718
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Aug 02, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 12:123253718
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 02, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 12:123253718
Benign
Hetero
Gene:
C2;CFB
Variant:
c.672C>T
(p.Tyr224=)
rsID: rs4151670
Ref Allele: C
Alt Allele: T
Freq: 1.885%uncommon
CADD: 11.65
ClinVar Submissions (1)
Hemolytic-uremic syndrome (HUS) is characterized by hemolytic anemia, thrombocytopenia, and renal failure caused by platelet thrombi in the microcirculation of the kidney and other organs. The onset of atypical HUS (aHUS) ranges from the neonatal period to adulthood. Genetic aHUS accounts for an estimated 60% of all aHUS. Individuals with genetic aHUS frequently experience relapse even after complete recovery following the presenting episode; 60% of genetic aHUS progresses to end-stage renal disease (ESRD).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 6:31947755
Complement component 2 deficiency is a disorder that causes the immune system to malfunction, resulting in a form of immunodeficiency. Immunodeficiencies are conditions in which the immune system is not able to protect the body effectively from foreign invaders such as bacteria and viruses. People with complement component 2 deficiency have a significantly increased risk of recurrent bacterial infections, specifically of the lungs (pneumonia), the membrane covering the brain and spinal cord (meningitis), and the blood (sepsis), which may be life-threatening. These infections most commonly occur in infancy and childhood and become less frequent in adolescence and adulthood.Complement component 2 deficiency is also associated with an increased risk of developing autoimmune disorders such as systemic lupus erythematosus (SLE) or vasculitis. Autoimmune disorders occur when the immune system malfunctions and attacks the body's tissues and organs. Between 10 and 20 percent of individuals with complement component 2 deficiency develop SLE. Females with complement component 2 deficiency are more likely to have SLE than affected males, but this is also true of SLE in the general population.The severity of complement component 2 deficiency varies widely. While some affected individuals experience recurrent infections and other immune system difficulties, others do not have any health problems related to the disorder.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 6:31947755
A nonspecific term denoting degeneration of the retinal pigment epithelium and/or retinal photoreceptor cells of the macula lutea.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 6:31947755
Likely benign
Hetero
Gene:
ABCA3
Variant:
c.-539+9C>A
rsID: rs45501400
Ref Allele: G
Alt Allele: T
Freq: 1.8938%uncommon
CADD: 14.68
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 16:2340564
Conflicting/Uncertain
Hetero
Gene:
TBC1D24
Variant:
c.*2395A>G
rsID: rs11543247
Ref Allele: A
Alt Allele: G
Freq: 1.9073%uncommon
CADD: 3.842
ClinVar Submissions (1)
TBC1D24-related disorders comprise a continuum of features that were originally described as distinct, recognized phenotypes: DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures). Profound sensorineural hearing loss, onychodystrophy, osteodystrophy, intellectual disability / developmental delay, and seizures. Familial infantile myoclonic epilepsy (FIME). Early-onset myoclonic seizures, focal epilepsy, dysarthria, and mild-to-moderate intellectual disability. Progressive myoclonus epilepsy (PME). Action myoclonus, tonic-clonic seizures, progressive neurologic decline, and ataxia. Early-infantile epileptic encephalopathy 16 (EIEE16). Epileptiform EEG abnormalities which themselves are believed to contribute to progressive disturbance in cerebral function. Autosomal recessive nonsyndromic hearing loss, DFNB86. Profound prelingual deafness. Autosomal dominant nonsyndromic hearing loss, DFNA65. Slowly progressive deafness with onset in the third decade, initially affecting the high frequencies.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 16:2503353
Conflicting/Uncertain
Hetero
Gene:
EIF2B5
Variant:
c.-103C>G
rsID: rs146922950
Ref Allele: C
Alt Allele: G
Freq: 1.9137%uncommon
CADD: 4.867
ClinVar Submissions (1)
Childhood ataxia with central nervous system hypomyelination/vanishing white matter disease (CACH/VWM) is characterized by ataxia, spasticity, and variable optic atrophy. The phenotypic range includes a prenatal/congenital form, a subacute infantile form (onset age <1 year), an early childhood onset form (onset age 1-5 years), a late childhood /juvenile onset form (onset age 5-15 years), and an adult onset form. The prenatal/congenital form is characterized by severe encephalopathy. In the later onset forms initial motor and intellectual development is normal or mildly delayed followed by neurologic deterioration with a chronic progressive or subacute course. Chronic progressive decline can be exacerbated by rapid deterioration during febrile illnesses or following head trauma or major surgical procedures, or by acute psychological stresses such as extreme fright.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 3:184135283
Conflicting/Uncertain
Hetero
Gene:
CDH23
Variant:
c.3664G>A
(p.Ala1222Thr)
rsID: rs41281316
Ref Allele: G
Alt Allele: A
Freq: 1.928%uncommon
CADD: 22.9
ClinVar Submissions (3)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Sep 23, 2013
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 10:71730553
Benign
Hetero
Gene:
EPG5
Variant:
c.3248C>T
(p.Ser1083Leu)
rsID: rs78339727
Ref Allele: G
Alt Allele: A
Freq: 1.9328%uncommon
CADD: 24.1
ClinVar Submissions (1)
Vici syndrome is a rare congenital multisystem disorder characterized by agenesis of the corpus callosum (ACC), cataracts, pigmentary defects, progressive cardiomyopathy, and variable immunodeficiency. Affected individuals also have profound psychomotor retardation and hypotonia due to a myopathy (summary by Finocchi et al., 2012).
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 18:45916574
Benign
Hetero
Gene:
TSHB
Variant:
c.40A>G
(p.Thr14Ala)
rsID: rs10776792
Ref Allele: A
Alt Allele: G
Freq: 1.9448%uncommon
CADD: 2.951
ClinVar Submissions (3)
Congenital hypothyroidism is a partial or complete loss of function of the thyroid gland (hypothyroidism) that affects infants from birth (congenital). The thyroid gland is a butterfly-shaped tissue in the lower neck. It makes iodine-containing hormones that play an important role in regulating growth, brain development, and the rate of chemical reactions in the body (metabolism). People with congenital hypothyroidism have lower-than-normal levels of these important hormones.Congenital hypothyroidism occurs when the thyroid gland fails to develop or function properly. In 80 to 85 percent of cases, the thyroid gland is absent, severely reduced in size (hypoplastic), or abnormally located. These cases are classified as thyroid dysgenesis. In the remainder of cases, a normal-sized or enlarged thyroid gland (goiter) is present, but production of thyroid hormones is decreased or absent. Most of these cases occur when one of several steps in the hormone synthesis process is impaired; these cases are classified as thyroid dyshormonogenesis. Less commonly, reduction or absence of thyroid hormone production is caused by impaired stimulation of the production process (which is normally done by a structure at the base of the brain called the pituitary gland), even though the process itself is unimpaired. These cases are classified as central (or pituitary) hypothyroidism.Signs and symptoms of congenital hypothyroidism result from the shortage of thyroid hormones. Affected babies may show no features of the condition, although some babies with congenital hypothyroidism are less active and sleep more than normal. They may have difficulty feeding and experience constipation. If untreated, congenital hypothyroidism can lead to intellectual disability and slow growth. In the United States and many other countries, all hospitals test newborns for congenital hypothyroidism. If treatment begins in the first two weeks after birth, infants usually develop normally.Congenital hypothyroidism can also occur as part of syndromes that affect other organs and tissues in the body. These forms of the condition are described as syndromic. Some common forms of syndromic hypothyroidism include Pendred syndrome, Bamforth-Lazarus syndrome, and brain-lung-thyroid syndrome.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:115033402
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:115033402
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:115033402
Benign
Hetero
Gene:
EDARADD
Variant:
c.308C>T
(p.Ser103Phe)
rsID: rs114632254
Ref Allele: C
Alt Allele: T
Freq: 1.9527%uncommon
CADD: 22.5
ClinVar Submissions (4)
Some ectodermal dysplasias are here classified as congenital disorders characterized by abnormal development in 2 or more ectodermal structures (hair, nails, teeth, and sweat glands) without other systemic findings. Hypohidrotic, or anhidrotic, ectodermal dysplasia (HED/EDA) is characterized by a triad of signs comprising sparse hair (hypotrichosis), abnormal or missing teeth (anodontia or hypodontia), and inability to sweat (anhidrosis or hypohidrosis). Typical clinical manifestations also include dryness of the skin, eyes, airways, and mucous membranes presumably due to the defective development of several exocrine glands. Hypohidrotic ectodermal dysplasia can be associated with dysmorphic features (forehead bumps, rings under the eyes, everted nose, and prominent lips) and occasionally with absent nipples (summary by Cluzeau et al., 2011).
Last Evaluated: Jul 20, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:236482309
Hypohidrotic ectodermal dysplasia (HED) is characterized by hypotrichosis (sparseness of scalp and body hair), hypohidrosis (reduced ability to sweat), and hypodontia (congenital absence of teeth). The cardinal features of classic HED become obvious during childhood. The scalp hair is thin, lightly pigmented, and slow-growing. Sweating, although present, is greatly deficient, leading to episodes of hyperthermia until the affected individual or family acquires experience with environmental modifications to control temperature. Only a few abnormally formed teeth erupt, and at a later-than-average age. Physical growth and psychomotor development are otherwise within normal limits. Mild HED is characterized by mild manifestations of any or all the characteristic features.
Last Evaluated: Jul 20, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:236482309
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 20, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:236482309
Benign/Likely benign
Hetero
Gene:
TRMU
Variant:
c.*8G>C
rsID: rs55905826
Ref Allele: G
Alt Allele: C
Freq: 1.9703%uncommon
CADD: 0.08
ClinVar Submissions (3)
Acute infantile liver failure resulting from TRMU mutation is a transient disorder of hepatic function. In addition to elevated liver enzymes, jaundice, vomiting, coagulopathy, and hyperbilirubinemia, the presence of increased serum lactate is consistent with a defect in mitochondrial respiratory function. With supportive care, patients who survive the initial acute episode can recover and show normal development (Zeharia et al., 2009). See also transient infantile mitochondrial myopathy (MMIT; 500009), which is a similar disorder. A more severe, permanent disorder with some overlapping features is associated with mitochondrial DNA depletion (251880). See ILFS1 (615438) for information on syndromic infantile liver failure.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 22:46357014
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 22:46357014
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 3
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 22:46357014
Conflicting/Uncertain
Hetero
Gene:
TMEM43
Variant:
c.909C>T
(p.Ser303=)
rsID: rs35100587
Ref Allele: C
Alt Allele: T
Freq: 1.987%uncommon
CADD: 7.566
ClinVar Submissions (5)
Arrhythmogenic right ventricular cardiomyopathy (ARVC) – previously referred to as arrhythmogenic right ventricular dysplasia (ARVD) – is characterized by progressive fibrofatty replacement of the myocardium that predisposes to ventricular tachycardia and sudden death in young individuals and athletes. It primarily affects the right ventricle, and it may also involve the left ventricle. The presentation of disease is highly variable even within families, and some affected individuals may not meet established clinical criteria. The mean age at diagnosis is 31 years (±13; range: 4-64 years).
Last Evaluated: Aug 15, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:14139206
Arrhythmogenic right ventricular cardiomyopathy (ARVC) – previously referred to as arrhythmogenic right ventricular dysplasia (ARVD) – is characterized by progressive fibrofatty replacement of the myocardium that predisposes to ventricular tachycardia and sudden death in young individuals and athletes. It primarily affects the right ventricle, and it may also involve the left ventricle. The presentation of disease is highly variable even within families, and some affected individuals may not meet established clinical criteria. The mean age at diagnosis is 31 years (±13; range: 4-64 years).
Last Evaluated: Aug 15, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:14139206
Last Evaluated: Aug 15, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:14139206
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 15, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:14139206
Benign/Likely benign
Hetero
Gene:
ELP1
Variant:
c.934G>A
(p.Glu312Lys)
rsID: rs1140064
Ref Allele: C
Alt Allele: T
Freq: 2.0332%uncommon
CADD: 18.9
ClinVar Submissions (4)
Familial dysautonomia (FD) affects the development and survival of sensory, sympathetic, and parasympathetic neurons. It is a debilitating disease present from birth. Neuronal degeneration progresses throughout life. Affected individuals have gastrointestinal dysfunction, vomiting crises, recurrent pneumonia, altered sensitivity to pain and temperature perception, and cardiovascular instability. About 40% of individuals have autonomic crises. Hypotonia contributes to delay in acquisition of motor milestones. Older individuals often have a broad-based and ataxic gait that deteriorates over time. Life expectancy is decreased.
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 9:108916228
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 9:108916228
Conflicting/Uncertain
Hetero
Gene:
EPAS1
Variant:
c.-471C>T
rsID: rs17039192
Ref Allele: C
Alt Allele: T
Freq: 2.0419%uncommon
CADD: 9.304
ClinVar Submissions (1)
Polycythemia that occurs in groups of related individuals.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:46297441
Benign
Hetero
Gene:
ABCA1
Variant:
c.-279C>G
rsID: rs111292742
Ref Allele: G
Alt Allele: C
Freq: 2.0427%uncommon
CADD: 7.065
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 9:104928121
Tangier disease is an autosomal recessive disorder characterized by markedly reduced levels of plasma high density lipoproteins (HDL) resulting in tissue accumulation of cholesterol esters. Clinical features include very large, yellow-orange tonsils, enlarged liver, spleen and lymph nodes, hypocholesterolemia, and abnormal chylomicron remnants (Brooks-Wilson et al., 1999).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 9:104928121
Likely benign
Hetero
Gene:
SLC5A5
Variant:
c.1626C>T
(p.Cys542=)
rsID: rs45602038
Ref Allele: C
Alt Allele: T
Freq: 2.0531%uncommon
CADD: 0.044
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 19:17888430
Conflicting/Uncertain
Hetero
Gene:
CASP8
Variant:
c.*411G>C
rsID: rs17860432
Ref Allele: G
Alt Allele: C
Freq: 2.0563%uncommon
CADD: 1.226
ClinVar Submissions (1)
Caspase 8 deficiency is a syndrome of lymphadenopathy and splenomegaly, marginal elevation of 'double-negative T cells' (DNT; T-cell receptor alpha/beta+, CD4-/CD8-), defective FAS-induced apoptosis, and defective T-, B-, and natural killer (NK)-cell activation, with recurrent bacterial and viral infections (summary by Madkaikar et al., 2011).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:201287005
Likely benign
Hetero
Gene:
LARS2
Variant:
c.972C>A
(p.His324Gln)
rsID: rs71645922
Ref Allele: C
Alt Allele: A
Freq: 2.0921%uncommon
CADD: 7.289
ClinVar Submissions (5)
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: May 14, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 3:45476581
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: May 14, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 3:45476581
Benign
Hetero
Gene:
ATP13A5
Variant:
c.1063C>T
(p.Gln355Ter)
rsID: rs74437357
Ref Allele: G
Alt Allele: A
Freq: 2.124%uncommon
CADD: 46
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 29, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 3:193334980
Likely benign
Hetero
Gene:
SRD5A2
Variant:
c.145G>A
(p.Ala49Thr)
rsID: rs9282858
Ref Allele: C
Alt Allele: T
Freq: 2.1391%uncommon
CADD: 19.39
ClinVar Submissions (4)
Last Evaluated: May 15, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:31580756
OMIM Allelic Variant: 607306.0012
Last Evaluated: May 15, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:31580756
OMIM Allelic Variant: 607306.0012
Last Evaluated: May 15, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:31580756
OMIM Allelic Variant: 607306.0012
Clinically Significant Benign
Hetero
Gene:
NSD2
Variant:
c.-43G>A
rsID: rs116056077
Ref Allele: G
Alt Allele: A
Freq: 2.151%uncommon
CADD: 1.708
ClinVar Submissions (1)
Wolf-Hirschhorn syndrome (WHS) is characterized by typical craniofacial features in infancy consisting of "Greek warrior helmet" appearance of the nose (wide bridge of the nose continuing to the forehead), microcephaly, high anterior hairline with prominent glabella, widely spaced eyes, epicanthus, highly arched eyebrows, short philtrum, downturned corners of the mouth, micrognathia, and poorly formed ears with pits/tags. All affected individuals have prenatal-onset growth deficiency followed by postnatal growth retardation and hypotonia with muscle underdevelopment. Developmental delay/intellectual disability of variable degree is present in all. Seizures occur in 90% to 100% of children with WHS. Other findings include skeletal anomalies (60%-70%), congenital heart defects (~50%), hearing loss (mostly conductive) (>40%), urinary tract malformations (25%), and structural brain abnormalities (33%).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 4:1899382
Likely benign
Hetero
Gene:
MYH3
Variant:
c.5457+3G>A
rsID: rs200954595
Ref Allele: C
Alt Allele: T
Freq: 2.1582%uncommon
CADD: 10.14
ClinVar Submissions (3)
A non-progressive finding characterized by multiple joint contractures found throughout the body at birth.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:10630285
Freeman-Sheldon syndrome (FSS), or DA2A, is phenotypically similar to DA1. In addition to contractures of the hands and feet, FSS is characterized by oropharyngeal abnormalities, scoliosis, and a distinctive face that includes a very small oral orifice (often only a few millimeters in diameter at birth), puckered lips, and an H-shaped dimple of the chin; hence, FSS has been called 'whistling face syndrome.' The limb phenotypes of DA1 and FSS may be so similar that they can only be distinguished by the differences in facial morphology (summary by Bamshad et al., 2009). For a general phenotypic description and a discussion of genetic heterogeneity of distal arthrogryposis, see DA1 (108120).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:10630285
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:10630285
Benign/Likely benign
Hetero
Gene:
KANSL1;MAPT
Variant:
c.*2810G>A
rsID: rs2158256
Ref Allele: G
Alt Allele: A
Freq: 2.1654%uncommon
CADD: 3.774
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 17:46026981
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 17:46026981
Likely benign
Hetero
Gene:
RHBDF2
Variant:
c.*580C>T
rsID: rs111924263
Ref Allele: G
Alt Allele: A
Freq: 2.1701%uncommon
CADD: 0.237
ClinVar Submissions (1)
Palmoplantar keratoderma (PPK) is a complex group of hereditary syndromes that have been classified into diffuse, punctate, and focal forms according to the pattern of hyperkeratosis on the palms and soles (Lucker et al., 1994). For a discussion of phenotypic and genetic heterogeneity of palmoplantar keratoderma, see epidermolytic PPK (144200).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 17:76471053
Benign
Hetero
Gene:
CFTR
Variant:
c.489+91A>G
rsID: rs56094102
Ref Allele: A
Alt Allele: G
Freq: 2.1733%uncommon
CADD: 0.352
ClinVar Submissions (1)
Cystic fibrosis (CF) is a multisystem disease affecting epithelia of the respiratory tract, exocrine pancreas, intestine, hepatobiliary system, and exocrine sweat glands. Morbidities include progressive obstructive lung disease with bronchiectasis, frequent hospitalizations for pulmonary disease, pancreatic insufficiency and malnutrition, recurrent sinusitis and bronchitis, and male infertility. Pulmonary disease is the major cause of morbidity and mortality in CF. Meconium ileus occurs at birth in 15%-20% of newborns with CF. More than 95% of males with CF are infertile. Congenital absence of the vas deferens (CAVD) is generally identified during evaluation of infertility or as an incidental finding at the time of a surgical procedure. Hypoplasia or aplasia of the vas deferens and seminal vesicles may occur either bilaterally or unilaterally. Testicular development and function and spermatogenesis are usually normal.
Last Evaluated: Dec 06, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:117531205
Likely benign
Hetero
Gene:
KRIT1
Variant:
c.*320C>T
rsID: rs112567410
Ref Allele: G
Alt Allele: A
Freq: 2.1765%uncommon
CADD: 1.937
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:92200416
Cerebral cavernous malformations (CCMs) are vascular malformations in the brain and spinal cord comprising closely clustered, enlarged capillary channels (caverns) with a single layer of endothelium without mature vessel wall elements or normal intervening brain parenchyma. The diameter of CCMs ranges from a few millimeters to several centimeters. CCMs increase or decrease in size and increase in number over time. Hundreds of lesions may be identified, depending on the person's age and the quality and type of brain imaging used. Although CCMs have been reported in infants and children, the majority become evident between the second and fifth decades with findings such as seizures, focal neurologic deficits, nonspecific headaches, and cerebral hemorrhage. Up to 50% of individuals with FCCM remain symptom free throughout their lives. Cutaneous vascular lesions are found in 9% of those with familial cerebral cavernous malformations (FCCM; see Diagnosis/testing) and retinal vascular lesions in almost 5%.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:92200416
Likely benign
Hetero
Gene:
SPAST
Variant:
c.*2399C>T
rsID: rs72796869
Ref Allele: C
Alt Allele: T
Freq: 2.1781%uncommon
CADD: 1.44
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:32156895
Likely benign
Hetero
Gene:
CHD7
Variant:
c.2442+38A>T
rsID: rs41272438
Ref Allele: A
Alt Allele: T
Freq: 2.198%uncommon
CADD: 0.217
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 8:60801631
Benign
Hetero
Gene:
GNAS
Variant:
c.940C>T
(p.Arg314Trp)
rsID: rs61749697
Ref Allele: C
Alt Allele: T
Freq: 2.2124%uncommon
CADD: 19.84
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Sep 19, 2013
Review Status: no assertion provided
Number of Submitters: 1
Clinical Significance: not provided
Assembly: GRCh38
Chromosome/Position: 20:58854392
Hetero
Gene:
SERPINF1
Variant:
c.395C>G
(p.Pro132Arg)
rsID: rs1804145
Ref Allele: C
Alt Allele: G
Freq: 2.2418%uncommon
CADD: 22.6
ClinVar Submissions (2)
Last Evaluated: Dec 15, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 2
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 17:1771140
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Dec 15, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 2
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 17:1771140
Conflicting/Uncertain
Hetero
Gene:
SOX9
Variant:
c.1113G>A
(p.Ala371=)
rsID: rs929651
Ref Allele: G
Alt Allele: A
Freq: 2.249%uncommon
CADD: 0.963
ClinVar Submissions (3)
Campomelic dysplasia (CD) is a skeletal dysplasia characterized by distinctive facies, Pierre Robin sequence with cleft palate, shortening and bowing of long bones, and clubfeet. Other findings include laryngotracheomalacia with respiratory compromise and ambiguous genitalia or normal female external genitalia in most individuals with a 46,XY karyotype. Many affected infants die in the neonatal period; additional problems identified in long-term survivors include short stature, cervical spine instability with cord compression, progressive scoliosis, and hearing impairment.
Last Evaluated: Apr 06, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 17:72123970
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Apr 06, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 17:72123970
Benign
Hetero
Gene:
RAD51B
Variant:
c.1094C>G
(p.Pro365Arg)
rsID: rs28908468
Ref Allele: C
Alt Allele: G
Freq: 2.2665%uncommon
CADD: 0.647
ClinVar Submissions (1)
Last Evaluated: Nov 27, 2017
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: drug response
Assembly: GRCh38
Chromosome/Position: 14:68594542
drug response
Hetero
Gene:
COL3A1
Variant:
c.2661+22T>A
rsID: rs28763878
Ref Allele: T
Alt Allele: A
Freq: 2.2673%uncommon
CADD: 10.16
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:189003809
Benign
Hetero
Gene:
PCNT
Variant:
c.9271A>G
(p.Ser3091Gly)
rsID: rs4818842
Ref Allele: A
Alt Allele: G
Freq: 2.2689%uncommon
CADD: 15.74
ClinVar Submissions (3)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 21:46438335
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 21:46438335
Benign/Likely benign
Hetero
Gene:
CD3G
Variant:
c.*308G>A
rsID: rs73018291
Ref Allele: G
Alt Allele: A
Freq: 2.3015%uncommon
CADD: 0.529
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 11:118353408
Conflicting/Uncertain
Hetero
Gene:
EP300
Variant:
c.2131+18T>A
rsID: rs9611506
Ref Allele: T
Alt Allele: A
Freq: 2.3023%uncommon
CADD: 0.83
ClinVar Submissions (2)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Apr 09, 2014
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 22:41146834
Benign
Hetero
Gene:
CEP164
Variant:
c.4119C>T
(p.Asn1373=)
rsID: rs73016324
Ref Allele: C
Alt Allele: T
Freq: 2.3207%uncommon
CADD: 0.136
ClinVar Submissions (2)
The nephronophthisis (NPH) phenotype is characterized by reduced renal concentrating ability, chronic tubulointerstitial nephritis, cystic renal disease, and progression to end-stage renal disease (ESRD) before age 30 years. Three age-based clinical subtypes are recongnized: infantile, juvenile, and adolescent/adult. Infantile NPH can present in utero with oligohydramnios sequence (limb contractures, pulmonary hypoplasia and facial dysmorphisms) or postnatally with renal manifestations that progress to ESRD before age 3 years. Juvenile NPH, the most prevalent subtype, typically presents with polydipsia and polyuria, growth retardation, chronic iron-resistant anemia, or other findings related to chronic kidney disease (CKD). Hypertension is typically absent due to salt wasting. ESRD develops at a median age of 13 years. Ultrasound findings are increased echogenicity, reduced corticomedullary differentiation, and renal cysts (in 50% of affected individuals). Histologic findings include tubulointerstitial fibrosis, thickened and disrupted tubular basement membrane, sporadic corticomedullary cysts, and normal or reduced kidney size. Adolescent/ adult NPH is clinically similar to juvenile NPH, but ESRD develops at a median age of 19 years. Within a subtype inter- and intrafamilial variability in rate of progression to ESRD is considerable. Approximately 80%-90% of individuals with the NPH phenotype have no extrarenal features (i.e., they have isolated NPH); ~10%-20% have extrarenal manifestations that constitute a recognizable syndrome (e.g., Joubert syndrome, Bardet-Biedl syndrome, Jeune syndrome and related skeletal disorders, Meckel-Gruber syndrome, Senior-Løken syndrome, Leber congenital amaurosis, COACH syndrome, and oculomotor apraxia, Cogan type).
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 11:117410850
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 11:117410850
Benign
Hetero
Gene:
GJA3
Variant:
c.543C>T
(p.Cys181=)
rsID: rs74607195
Ref Allele: G
Alt Allele: A
Freq: 2.3278%uncommon
CADD: 14.79
ClinVar Submissions (3)
Last Evaluated: Nov 01, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 13:20142746
Mutations in the GJA3 gene have been found to cause multiple types of cataract, which have been described as zonular pulverulent, posterior polar, nuclear coralliform, embryonal nuclear, and Coppock-like. The preferred title/symbol for this entry was formerly 'Cataract, Zonular Pulverulent 3; CZP3.'
Last Evaluated: Nov 01, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 13:20142746
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Nov 01, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 13:20142746
Benign
Hetero
Gene:
PPP2R1A
Variant:
c.78+113C>T
rsID: rs41275796
Ref Allele: C
Alt Allele: T
Freq: 2.3461%uncommon
CADD: 18.68
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Sep 19, 2013
Review Status: no assertion provided
Number of Submitters: 1
Clinical Significance: not provided
Assembly: GRCh38
Chromosome/Position: 19:52190287
Hetero
Gene:
KIT
Variant:
c.1638A>G
(p.Lys546=)
rsID: rs55986963
Ref Allele: A
Alt Allele: G
Freq: 2.3621%uncommon
CADD: 18.38
ClinVar Submissions (3)
Gastrointestinal stromal tumors are mesenchymal tumors found in the gastrointestinal tract that originate from the interstitial cells of Cajal, the pacemaker cells that regulate peristalsis in the digestive tract. Approximately 70% of GISTs develop in the stomach, 20% in the small intestine, and less than 10% in the esophagus, colon, and rectum. GISTs are typically more cellular than other gastrointestinal sarcomas. They occur predominantly in patients who are 40 to 70 years old but in rare cases may occur in younger persons (Miettinen et al., 1999, 1999). GISTs can also be seen in neurofibromatosis-1 (NF1; 162200) due to mutations in the NF1 gene, and are thus distinct from the GISTs described here. Sandberg and Bridge (2002) reviewed the cytogenetics and molecular genetics of gastrointestinal stromal tumors. Coffey et al. (2007) reviewed the clinical features, pathogenesis, and molecular treatments of Menetrier disease (137280) and GIST, both of which are hyperproliferative disorders of the stomach caused by dysregulated receptor tyrosine kinases.
Last Evaluated: Aug 16, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 4:54727315
Mastocytosis, or mast cell disease, is a heterogeneous group of clinical disorders characterized by the abnormal accumulation of mast cells in various tissues, especially in the skin and hematopoietic organs. Mastocytosis usually appears in infancy or early adulthood. In most pediatric cases, the disease is limited to the skin, but it can be associated with systemic symptoms due to the release of mediators from mast cells, even when there is no systemic infiltration. It usually has a good prognosis, with substantial improvement or spontaneous resolution before puberty. In rare cases, the disease may remain active through adolescence as a systemic adult mastocytosis. Cutaneous mastocytosis is characterized by macules, papules, nodules, or diffuse infiltration of the skin, often associated with localized hyperpigmentation. Gentle rubbing of the lesions induces histamine release from mechanically activated mast cells, causing local wheals, erythema, and often pruritus, a phenomenon termed the 'Darier sign.' In contrast to childhood-onset mastocytosis, adult-onset mastocytosis often persists for the lifetime of the patient and is also more likely to be a severe and systemic disease involving numerous organs. In some cases, it is associated with a clonal hematologic non-mast-cell lineage disease, such as a myelodysplastic or myeloproliferative disorder. Adult-onset mastocytosis can also lead to the rare mast cell leukemia, which carries a high risk of mortality (summary by Bodemer et al., 2010 and Kambe et al., 2010).
Last Evaluated: Aug 16, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 4:54727315
Piebaldism is a rare autosomal dominant trait characterized by the congenital absence of melanocytes in affected areas of the skin and hair. A white forelock of hair, often triangular in shape, may be the only manifestation, or both the hair and the underlying forehead may be involved. The eyebrows and eyelashes may be affected. Irregularly shaped white patches may be observed on the face, trunk, and extremities, usually in a symmetrical distribution. Typically, islands of hyperpigmentation are present within and at the border of depigmented areas (summary by Thomas et al., 2004).
Last Evaluated: Aug 16, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 4:54727315
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 16, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 4:54727315
Benign/Likely benign
Hetero
Gene:
FKTN
Variant:
c.1044+44A>G
rsID: rs118064041
Ref Allele: A
Alt Allele: G
Freq: 2.3676%uncommon
CADD: 4.683
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 9:105618136
Benign
Hetero
Gene:
FUS
Variant:
c.*910C>T
rsID: rs118018900
Ref Allele: C
Alt Allele: T
Freq: 2.3804%uncommon
CADD: 0.409
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 16:31192348
Likely benign
Hetero
Gene:
VCAN
Variant:
c.9882C>T
(p.Val3294=)
rsID: rs308365
Ref Allele: C
Alt Allele: T
Freq: 2.3931%uncommon
CADD: 15.49
ClinVar Submissions (4)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 5:83579981
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 5:83579981
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 5:83579981
Benign
Hetero
Gene:
ADAMTS2
Variant:
c.936C>T
(p.Asn312=)
rsID: rs35462609
Ref Allele: G
Alt Allele: A
Freq: 2.4043%uncommon
CADD: 4.17
ClinVar Submissions (3)
Dermatosparaxis (meaning 'tearing of skin') is an autosomal recessive disorder of connective tissue resulting from deficiency of procollagen peptidase, an enzyme that aids in the processing of type I procollagen. The disorder and the responsible biochemical defect was first observed in cattle (Lapiere et al., 1971). Lapiere and Nusgens (1993) reviewed the discovery of dermatosparaxis in cattle, the elucidation of the disorder, its occurrence in other animals, and the delayed recognition of the disorder in the human.
Last Evaluated: Aug 04, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 5:179181111
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 04, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 5:179181111
Benign/Likely benign
Hetero
Gene:
B9D1
Variant:
c.-70G>A
rsID: rs2296978
Ref Allele: C
Alt Allele: T
Freq: 2.413%uncommon
CADD: 16.59
ClinVar Submissions (2)
A rare, lethal, autosomal recessive inherited syndrome characterized by pulmonary hypoplasia, central nervous system malformations, and hepatic malformations.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:19362639
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:19362639
Benign/Likely benign
Hetero
Gene:
DYNC2H1
Variant:
c.4728C>G
(p.Asn1576Lys)
rsID: rs72989738
Ref Allele: C
Alt Allele: G
Freq: 2.4385%uncommon
CADD: 5.514
ClinVar Submissions (4)
Asphyxiating thoracic dystrophy, also known as Jeune syndrome, is an inherited disorder of bone growth characterized by a narrow chest, short ribs, shortened bones in the arms and legs, short stature, and extra fingers and toes (polydactyly). Additional skeletal abnormalities can include unusually shaped collarbones (clavicles) and pelvic bones, and and cone-shaped ends of the long bones in the arms and legs. Many infants with this condition are born with an extremely narrow, bell-shaped chest that can restrict the growth and expansion of the lungs. Life-threatening problems with breathing result, and people with asphyxiating thoracic dystrophy may live only into infancy or early childhood. However, in people who survive beyond the first few years, the narrow chest and related breathing problems can improve with age.Some people with asphyxiating thoracic dystrophy are born with less severe skeletal abnormalities and have only mild breathing difficulties, such as rapid breathing or shortness of breath. These individuals may live into adolescence or adulthood. After infancy, people with this condition may develop life-threatening kidney (renal) abnormalities that cause the kidneys to malfunction or fail. Heart defects and a narrowing of the airway (subglottic stenosis) are also possible. Other, less common features of asphyxiating thoracic dystrophy include liver disease, fluid-filled sacs (cysts) in the pancreas, dental abnormalities, and an eye disease called retinal dystrophy that can lead to vision loss.
Last Evaluated: Jul 27, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 11:103166014
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 27, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 11:103166014
Benign
Hetero
Gene:
NFU1
Variant:
c.286C>T
(p.Arg96Cys)
rsID: rs74637005
Ref Allele: G
Alt Allele: A
Freq: 2.4505%uncommon
CADD: 23.1
ClinVar Submissions (3)
Syndrome caused by impairment of mitochondria. Whilst mitochondrial disorders may be caused by impairment of a single stage of energy production, individuals with multiple mitochondrial dysfunctions syndrome have reduced function of more than one stage. Symptoms begin in early life and affected individuals usually do not live past infancy. Symptoms include encephalopathy, hypotonia, seizures and psychomotor delay. Most affected babies have lactic acidosis that can be life threatening.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:69423598
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:69423598
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:69423598
Benign/Likely benign
Hetero
Gene:
CLN5
Variant:
c.234C>G
(p.Ala78=)
rsID: rs138037471
Ref Allele: C
Alt Allele: G
Freq: 2.4791%uncommon
CADD: 6.797
ClinVar Submissions (8)
Last Evaluated: Aug 16, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 13:76992185
The neuronal ceroid-lipofuscinoses (NCLs) are a group of inherited, neurodegenerative, lysosomal storage disorders characterized by progressive intellectual and motor deterioration, seizures, and early death. Visual loss is a feature of most forms. Clinical phenotypes have been characterized traditionally according to the age of onset and order of appearance of clinical features into infantile, late-infantile, juvenile, adult, and Northern epilepsy (also known as progressive epilepsy with mental retardation [EPMR]). There is however genetic and allelic heterogeneity; a proposed new nomenclature and classification system has been developed to take into account both the responsible gene and the age at disease onset; for example, CLN1 disease, infantile onset and CLN1 disease, juvenile onset are both caused by pathogenic variants in PPT1 but with differing age of onset. The most prevalent NCLs are CLN3 disease, classic juvenile and CLN2 disease, classic late infantile (although prevalence varies by ethnicity and country of family origin): CLN2 disease, classic late infantile. The first symptoms typically appear between age two and four years, usually starting with epilepsy, followed by regression of developmental milestones, myoclonic ataxia, and pyramidal signs. Visual impairment typically appears at age four to six years and rapidly progresses to light /dark awareness only. Life expectancy ranges from age six years to early teenage. CLN3 disease, classic juvenile. Onset is usually between ages four and ten years. Rapidly progressing visual loss resulting in severe visual impairment within one to two years is often the first clinical sign. Epilepsy with generalized tonic-clonic seizures and/or complex-partial seizures typically appears around age ten years. Life expectancy ranges from the late teens to the 30s. Other forms of NCL may present with behavior changes, epilepsy, visual impairment, or slowing of developmental progress and then loss of skills. The course may be extremely variable. Some genotype-phenotype information is available.
Last Evaluated: Aug 16, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 13:76992185
Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as EPILEPSY or "seizure disorder."
Last Evaluated: Aug 16, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 13:76992185
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Aug 16, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 13:76992185
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 16, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 13:76992185
Benign/Likely benign
Hetero
Gene:
RIMS1
Variant:
c.3470C>T
(p.Pro1157Leu)
rsID: rs41265501
Ref Allele: C
Alt Allele: T
Freq: 2.5038%uncommon
CADD: 24.6
ClinVar Submissions (2)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:72274420
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:72274420
Benign/Likely benign
Hetero
Gene:
MYLK
Variant:
c.4194C>T
(p.His1398=)
rsID: rs17298941
Ref Allele: G
Alt Allele: A
Freq: 2.511%uncommon
CADD: 5.023
ClinVar Submissions (7)
Last Evaluated: Aug 03, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:123657220
Last Evaluated: Aug 03, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:123657220
Familial thoracic aortic aneurysm and dissection (familial TAAD) involves problems with the aorta, which is the large blood vessel that distributes blood from the heart to the rest of the body. Familial TAAD affects the upper part of the aorta, near the heart. This part of the aorta is called the thoracic aorta because it is located in the chest (thorax). Other vessels that carry blood from the heart to the rest of the body (arteries) can also be affected.In familial TAAD, the aorta can become weakened and stretched (aortic dilatation), which can lead to a bulge in the blood vessel wall (an aneurysm). Aortic dilatation may also lead to a sudden tearing of the layers in the aorta wall (aortic dissection), allowing blood to flow abnormally between the layers. These aortic abnormalities are potentially life-threatening because they can decrease blood flow to other parts of the body such as the brain or other vital organs, or cause the aorta to break open (rupture).The occurrence and timing of these aortic abnormalities vary, even within the same affected family. They can begin in childhood or not occur until late in life. Aortic dilatation is generally the first feature of familial TAAD to develop, although in some affected individuals dissection occurs with little or no aortic dilatation.Aortic aneurysms usually have no symptoms. However, depending on the size, growth rate, and location of these abnormalities, they can cause pain in the jaw, neck, chest, or back; swelling in the arms, neck, or head; difficult or painful swallowing; hoarseness; shortness of breath; wheezing; a chronic cough; or coughing up blood. Aortic dissections usually cause severe, sudden chest or back pain, and may also result in unusually pale skin (pallor), a very faint pulse, numbness or tingling (paresthesias) in one or more limbs, or paralysis.Familial TAAD may not be associated with other signs and symptoms. However, some individuals in affected families show mild features of related conditions called Marfan syndrome or Loeys-Dietz syndrome. These features include tall stature, stretch marks on the skin, an unusually large range of joint movement (joint hypermobility), and either a sunken or protruding chest. Occasionally, people with familial TAAD develop aneurysms in the brain or in the section of the aorta located in the abdomen (abdominal aorta). Some people with familial TAAD have heart abnormalities that are present from birth (congenital). Affected individuals may also have a soft out-pouching in the lower abdomen (inguinal hernia), an abnormal curvature of the spine (scoliosis), or a purplish skin discoloration (livedo reticularis) caused by abnormalities in the tiny blood vessels of the skin (dermal capillaries). However, these conditions are also common in the general population. Depending on the genetic cause of familial TAAD in particular families, they may have an increased risk of developing blockages in smaller arteries, which can lead to heart attack and stroke.
Last Evaluated: Aug 03, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:123657220
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Aug 03, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:123657220
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 03, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:123657220
Benign/Likely benign
Hetero
Gene:
OCLN
Variant:
c.699G>A
(p.Leu233=)
rsID: rs35107257
Ref Allele: G
Alt Allele: A
Freq: 2.5142%uncommon
CADD: 2.926
ClinVar Submissions (2)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jan 30, 2014
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 5:69509789
Benign
Hetero
Gene:
KIF5C
Variant:
c.501+8G>A
rsID: rs13411910
Ref Allele: G
Alt Allele: A
Freq: 2.5397%uncommon
CADD: 6.231
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Feb 19, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:148941998
Benign
Hetero
Gene:
ERCC3
Variant:
c.-69C>T
rsID: rs9282675
Ref Allele: G
Alt Allele: A
Freq: 2.5651%uncommon
CADD: 2.099
ClinVar Submissions (1)
Xeroderma pigmentosum (XP) is characterized by: Sun sensitivity (severe sunburn with blistering, persistent erythema on minimal sun exposure in ~60% of affected individuals), with marked freckle-like pigmentation of the face before age two years in most affected individuals; Sunlight-induced ocular involvement (photophobia, keratitis, atrophy of the skin of the lids); Greatly increased risk of sunlight-induced cutaneous neoplasms (basal cell carcinoma, squamous cell carcinoma, melanoma). Approximately 25% of affected individuals have neurologic manifestations (acquired microcephaly, diminished or absent deep tendon stretch reflexes, progressive sensorineural hearing loss, and progressive cognitive impairment). The most common causes of death are skin cancer, neurologic degeneration, and internal cancer. The median age at death in persons with XP with neurodegeneration (29 years) was found to be younger than that in persons with XP without neurodegeneration (37 years).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:127294150
Likely benign
Hetero
Gene:
TNPO3
Variant:
c.321+16C>T
rsID: rs17424179
Ref Allele: G
Alt Allele: A
Freq: 2.5882%uncommon
CADD: 5.856
ClinVar Submissions (2)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jan 19, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 7:129017941
Benign
Hetero
Gene:
GRIN2A
Variant:
c.*4739T>C
rsID: rs111346223
Ref Allele: A
Alt Allele: G
Freq: 2.5906%uncommon
CADD: 1.855
ClinVar Submissions (1)
GRIN2A-related speech disorders and epilepsy are characterized by speech disorders in all affected individuals and a range of epilepsy syndromes present in about 90%. Severe speech disorders observed can include dysarthria and speech dyspraxia, and both receptive and expressive language delay/regression; more mildly affected individuals may display subtly impaired intelligibility of conversational speech. Epilepsy features include seizure onset usually between ages three and six years, focal epilepsy with language and/or global developmental regression, and electroencephalogram (EEG) showing continuous spike-and-wave discharges in sleep or very active centrotemporal discharges. Seizure types include seizures associated with aura of perioral paresthesia, focal or focal motor seizures (often evolving to generalized tonic-clonic), and atypical absence seizures. Epilepsy syndromes can include: Landau-Kleffner syndrome (LKS), epileptic encephalopathy with continuous spike-and-wave during sleep (ECSWS), childhood epilepsy with centrotemporal spikes (CECTS), atypical childhood epilepsy with centrotemporal spikes (ACECTS), autosomal dominant rolandic epilepsy with speech dyspraxia (ADRESD), and infantile-onset epileptic encephalopathy.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 16:9758410
Benign
Hetero
Gene:
NOTCH3
Variant:
c.1140T>C
(p.Pro380=)
rsID: rs61749020
Ref Allele: A
Alt Allele: G
Freq: 2.6233%uncommon
CADD: 5.307
ClinVar Submissions (3)
CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is characterized by mid-adult onset of recurrent ischemic stroke, cognitive decline progressing to dementia, a history of migraine with aura, mood disturbance, apathy, and diffuse white matter lesions and subcortical infarcts on neuroimaging.
Last Evaluated: May 31, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 19:15189325
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: May 31, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 19:15189325
Benign/Likely benign
Hetero
Gene:
PDZD7
Variant:
c.2132A>G
(p.His711Arg)
rsID: rs34616847
Ref Allele: T
Alt Allele: C
Freq: 2.6376%uncommon
CADD: 16.71
ClinVar Submissions (3)
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: May 29, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 10:101010757
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: May 29, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 10:101010757
Benign
Hetero
Gene:
RYR2
Variant:
c.*647C>T
rsID: rs16835894
Ref Allele: C
Alt Allele: T
Freq: 2.6432%uncommon
CADD: 0.449
ClinVar Submissions (1)
Arrhythmogenic right ventricular cardiomyopathy (ARVC) – previously referred to as arrhythmogenic right ventricular dysplasia (ARVD) – is characterized by progressive fibrofatty replacement of the myocardium that predisposes to ventricular tachycardia and sudden death in young individuals and athletes. It primarily affects the right ventricle, and it may also involve the left ventricle. The presentation of disease is highly variable even within families, and some affected individuals may not meet established clinical criteria. The mean age at diagnosis is 31 years (±13; range: 4-64 years).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:237833294
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is characterized by episodic syncope occurring during exercise or acute emotion in individuals without structural cardiac abnormalities. The underlying cause of these episodes is the onset of fast ventricular tachycardia (bidirectional or polymorphic). Spontaneous recovery may occur when these arrhythmias self-terminate. In other instances, ventricular tachycardia may degenerate into ventricular fibrillation and cause sudden death if cardiopulmonary resuscitation is not readily available. The mean age of onset of symptoms (usually a syncopal episode) is between age seven and twelve years; onset as late as the fourth decade of life has been reported. If untreated, CPVT is highly lethal, as approximately 30% of affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. Sudden death may be the first manifestation of the disease.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:237833294
Likely benign
Hetero
Gene:
MAGI2
Variant:
c.3915G>A
(p.Gln1305=)
rsID: rs117054456
Ref Allele: C
Alt Allele: T
Freq: 2.6551%uncommon
CADD: 16.4
ClinVar Submissions (3)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jan 30, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 7:78019768
Benign
Hetero
Gene:
SUFU
Variant:
c.*1675G>A
rsID: rs41287466
Ref Allele: G
Alt Allele: A
Freq: 2.6711%uncommon
CADD: 7.694
ClinVar Submissions (1)
Medulloblastoma is the most common brain tumor in children. It accounts for 16% of all pediatric brain tumors, and 40% of all cerebellar tumors in childhood are medulloblastoma. Medulloblastoma occurs bimodally, with peak incidences between 3 and 4 years and 8 and 9 years of age. Approximately 10 to 15% of medulloblastomas are diagnosed in infancy. Medulloblastoma accounts for less than 1% of central nervous system (CNS) tumors in adults, with highest incidence in adults 20 to 34 years of age. In 1 to 2% of patients, medulloblastoma is associated with Gorlin syndrome (109400), a nevoid basal carcinoma syndrome. Medulloblastoma also occurs in up to 40% of patients with Turcot syndrome (276300). Medulloblastoma is thought to arise from neural stem cell precursors in the granular cell layer of the cerebellum. Standard treatment includes surgery, chemotherapy, and, depending on the age of the patient, radiation therapy (Crawford et al., 2007).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 10:102631830
Likely benign
Hetero
Gene:
HEXB
Variant:
c.185C=
(p.Ser62=)
rsID: rs820878
Ref Allele: T
Alt Allele: C
Freq: 2.6862%uncommon
CADD: 13.58
ClinVar Submissions (2)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 28, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 5:74685445
Insufficiently evaluated pathogenic — This variant was seen as a compound heterozygote with a 25kb deletion in the same gene in an individual with Infantile Sandhoff disease.
Benign
Hetero
Gene:
DNAH7
Variant:
c.2619C>G
(p.Val873=)
rsID: rs115124743
Ref Allele: G
Alt Allele: C
Freq: 2.6902%uncommon
CADD: 2.548
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 29, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:195960532
Benign
Hetero
Gene:
GNPTAB
Variant:
c.3602+8C>A
rsID: rs79493678
Ref Allele: G
Alt Allele: T
Freq: 2.6989%uncommon
CADD: 0.892
ClinVar Submissions (5)
Last Evaluated: May 01, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:101753364
Last Evaluated: May 01, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:101753364
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: May 01, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:101753364
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: May 01, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:101753364
Benign/Likely benign
Hetero
Gene:
GRIN2A
Variant:
c.*8978G>C
rsID: rs79818496
Ref Allele: C
Alt Allele: G
Freq: 2.7069%uncommon
CADD: 5.606
ClinVar Submissions (1)
GRIN2A-related speech disorders and epilepsy are characterized by speech disorders in all affected individuals and a range of epilepsy syndromes present in about 90%. Severe speech disorders observed can include dysarthria and speech dyspraxia, and both receptive and expressive language delay/regression; more mildly affected individuals may display subtly impaired intelligibility of conversational speech. Epilepsy features include seizure onset usually between ages three and six years, focal epilepsy with language and/or global developmental regression, and electroencephalogram (EEG) showing continuous spike-and-wave discharges in sleep or very active centrotemporal discharges. Seizure types include seizures associated with aura of perioral paresthesia, focal or focal motor seizures (often evolving to generalized tonic-clonic), and atypical absence seizures. Epilepsy syndromes can include: Landau-Kleffner syndrome (LKS), epileptic encephalopathy with continuous spike-and-wave during sleep (ECSWS), childhood epilepsy with centrotemporal spikes (CECTS), atypical childhood epilepsy with centrotemporal spikes (ACECTS), autosomal dominant rolandic epilepsy with speech dyspraxia (ADRESD), and infantile-onset epileptic encephalopathy.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 16:9754171
Benign
Hetero
Gene:
NDUFS1
Variant:
c.*158T>C
rsID: rs3770989
Ref Allele: A
Alt Allele: G
Freq: 2.7101%uncommon
CADD: 13.09
ClinVar Submissions (1)
Leigh syndrome is a clinically and genetically heterogeneous disorder resulting from defective mitochondrial energy generation. It most commonly presents as a progressive and severe neurodegenerative disorder with onset within the first months or years of life, and may result in early death. Affected individuals usually show global developmental delay or developmental regression, hypotonia, ataxia, dystonia, and ophthalmologic abnormalities, such as nystagmus or optic atrophy. The neurologic features are associated with the classic findings of T2-weighted hyperintensities in the basal ganglia and/or brainstem on brain imaging. Leigh syndrome can also have detrimental multisystemic affects on the cardiac, hepatic, gastrointestinal, and renal organs. Biochemical studies in patients with Leigh syndrome tend to show increased lactate and abnormalities of mitochondrial oxidative phosphorylation. Thus, Leigh syndrome may be a clinical feature of a primary deficiency of any of the mitochondrial respiratory chain complexes: complex I deficiency (see 252010), complex II deficiency (see 252011), complex III deficiency (see 124000), complex IV deficiency (cytochrome c oxidase; see 220110), or complex V deficiency (see 604273) (summary by Lake et al., 2015). Genetic Heterogeneity of Leigh Syndrome Mutations in complex I genes include mitochondrial-encoded MTND2 (516001), MTND3 (516002), MTND5 (516005), and MTND6 (516006), the nuclear-encoded NDUFS1 (157655), NDUFS3 (603846), NDUFS4 (602694), NDUFS7 (601825), NDUFS8 (602141), NDUFA2 (602137), NDUFA9 (603834), NDUFA10 (603835), NDUFA12 (614530), NDUFAF6 (612392), and NDUFAF5 (612360). Mutation in the MTFMT gene (611766), which is involved in mitochondrial translation, has also been reported with complex I deficiency. A mutation has been found in a complex III gene: BCS1L (603647), which is involved in the assembly of complex III. Mutations in complex IV genes include mitochondrial-encoded MTCO3 (516050) and nuclear-encoded COX10 (602125), COX15 (603646), SCO2 (604272), SURF1 (185620), which is involved in the assembly of complex IV, TACO1 (612958), and PET100 (614770). A mutation has been found in a complex V gene: the mitochondrial-encoded MTATP6 (516060). Mutations in genes encoding mitochondrial tRNA proteins have also been identified in patients with Leigh syndrome: see MTTV (590105), MTTK (590060), MTTW (590095), and MTTL1 (590050). Leigh syndrome may also be caused by mutations in components of the pyruvate dehydrogenase complex (e.g., DLD, 238331 and PDHA1, 300502). The French Canadian (or Saguenay-Lac-Saint-Jean) type of Leigh syndrome with COX deficiency (LSFC; 220111) is caused by mutation in the LRPPRC gene (607544). Deficiency of coenzyme Q10 (607426) can present as Leigh syndrome.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 2:206124027
Isolated complex I deficiency is the most common enzymatic defect of the oxidative phosphorylation disorders (McFarland et al., 2004; Kirby et al., 2004). It causes a wide range of clinical disorders, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, nonspecific encephalopathy, hypertrophic cardiomyopathy, myopathy, liver disease, Leigh syndrome (see 256000), Leber hereditary optic neuropathy (535000), and some forms of Parkinson disease (see 556500) (Loeffen et al., 2000; Pitkanen et al., 1996; Robinson, 1998). Genetic Heterogeneity of Complex I Deficiency Mitochondrial complex I deficiency shows extreme genetic heterogeneity and can be caused by mutation in nuclear-encoded genes or in mitochondrial-encoded genes. There are no obvious genotype-phenotype correlations, and inference of the underlying basis from the clinical or biochemical presentation is difficult, if not impossible (summary by Haack et al., 2012). However, the majority of cases are caused by mutations in nuclear-encoded genes (Loeffen et al., 2000; Triepels et al., 2001). Complex I deficiency resulting from mutation in nuclear-encoded genes include MC1DN1, caused by mutation in the NDUFS4 gene (602694); MC1DN2 (618222), caused by mutation in the NDUFS8 gene (602141); MC1DN3 (618224), caused by mutation in the NDUFS7 gene (601825); MC1DN4 (618225), caused by mutation in the NDUFV1 gene (161015); MC1DN5 (618226), caused by mutation in the NDUFS1 gene (157655); MC1DN6 (618228), caused by mutation in the NDUFS2 gene (602985); MC1DN7 (618229), caused by mutation in the NDUFV2 gene (600532); MC1DN8 (618230), caused by mutation in the NDUFS3 gene (603846); MC1DN9 (618232), caused by mutation in the NDUFS6 gene (603848); MC1DN10 (618233), caused by mutation in the NDUFAF2 gene (609653); MC1DN11 (618234), caused by mutation in the NDUFAF1 gene (606934); MC1DN12 (301020), caused by mutation in the NDUFA1 gene (300078); MC1DN13 (618235), caused by mutation in the NDUFA2 gene (602137); MC1DN14 (618236), caused by mutation in the NDUFA11 gene (612638); MC1DN15 (618237), caused by mutation in the NDUFAF4 gene (611776); MC1DN16 (618238), caused by mutation in the NDUFAF5 gene (612360); MC1DN17 (618239), caused by mutation in the NDUFAF6 gene (612392); MC1DN18 (618240), caused by mutation in the NDUFAF3 gene (612911); MC1DN19 (618241), caused by mutation in the FOXRED1 gene (613622); MC1DN20 (611126), caused by mutation in the ACAD9 gene (611103); MC1DN21 (618242), caused by mutation in the NUBPL gene (613621); MC1DN22 (618243), caused by mutation in the NDUFA10 gene (603835); MC1DN23 (618244), caused by mutation in the NDUFA12 gene (614530); MC1DN24 (618245), caused by mutation in the NDUFB9 gene (601445); MC1DN25 (618246), caused by mutation in the NDUFB3 gene (603839); MC1DN26 (618247), caused by mutation in the NDUFA9 gene (603834); MC1DN27 (618248), caused by mutation in the MTFMT gene (611766); MC1DN28 (618249), caused by mutation in the NDUFA13 gene (609435); MC1DN29 (618250), caused by mutation in the TMEM126B gene (615533); MC1DN30 (301021), caused by mutation in the NDUFB11 gene (300403); MC1DN31 (618251), caused by mutation in the TIMMDC1 gene (615534); MC1DN32 (618252), caused by mutation in the NDUFB8 gene (602140); and MC1DN33 (618253), caused by mutation in the NDUFA6 gene (602138). Complex I deficiency with mitochondrial inheritance has been associated with mutation in 6 mitochondrial-encoded components of complex I: MTND1 (516000), MTND2 (516001), MTND3 (516002), MTND4 (516003), MTND5 (516005), MTND6 (516006). Most of these patients have a phenotype of Leber hereditary optic neuropathy (LHON; 535000) or Leigh syndrome. Features of complex I deficiency may also be caused by mutation in other mitochondrial genes, including MTTS2 (590085).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 2:206124027
Conflicting/Uncertain
Hetero
Gene:
TYROBP
Variant:
c.123C>G
(p.Gly41=)
rsID: rs111477177
Ref Allele: G
Alt Allele: C
Freq: 2.7141%uncommon
CADD: 1.337
ClinVar Submissions (1)
Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL) is characterized by fractures (resulting from radiologically demonstrable polycystic osseous lesions), frontal lobe syndrome, and progressive presenile dementia beginning in the fourth decade. The clinical course of PLOSL can be divided into four stages: (1) The latent stage is characterized by normal early development. (2) The osseous stage (3rd decade of life) is characterized by pain and tenderness, mostly in ankles and feet, usually following strain or injury. Fractures are typically diagnosed several years later, most commonly in the bones of the extremities. (3) In the early neurologic stage (4th decade of life), a change of personality begins to develop insidiously. Affected individuals show a frontal lobe syndrome (loss of judgment, euphoria, loss of social inhibitions, disturbance of concentration, and lack of insight, libido, and motor persistence) leading to serious social problems. (4) The late neurologic stage is characterized by progressive dementia and loss of mobility. Death usually occurs before age 50 years.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 19:35907552
Likely benign
Hetero
Gene:
IMPDH1
Variant:
c.*228G>A
rsID: rs72624976
Ref Allele: C
Alt Allele: T
Freq: 2.7244%uncommon
CADD: 0.177
ClinVar Submissions (1)
Leber congenital amaurosis comprises a group of early-onset childhood retinal dystrophies characterized by vision loss, nystagmus, and severe retinal dysfunction. Patients usually present at birth with profound vision loss and pendular nystagmus. Electroretinogram (ERG) responses are usually nonrecordable. Other clinical findings may include high hypermetropia, photodysphoria, oculodigital sign, keratoconus, cataracts, and a variable appearance to the fundus (summary by Chung and Traboulsi, 2009). Genetic Heterogeneity of Leber Congenital Amaurosis LCA2 (204100) is caused by mutation in the RPE65 gene (RPE65; 180069) on chromosome 1p31. LCA3 (604232) is caused by mutation in the SPATA7 gene (609868) on chromosome 14q31. LCA4 (604393) is caused by mutation in the AIPL1 gene (604392) on chromosome 17p13. LCA5 (604537) is caused by mutation in the LCA5 gene (611408) on chromosome 6q14. LCA6 (613826) is caused by mutation in the RPGRIP1 gene (605446) on chromosome 14q11. LCA7 (613829) is caused by mutation in the CRX gene (602225) on chromosome 19q13. LCA8 (613835) is caused by mutation in the CRB1 gene (604210) on chromosome 1q31. LCA9 (608553) is caused by mutation in the NMNAT1 gene (608700) on chromosome 1p36. LCA10 (611755) is caused by mutation in the CEP290 gene (610142) on chromosome 12q21 and may account for as many as 21% of cases of LCA. LCA11 (613837) is caused by mutation in the IMPDH1 gene (146690) on chromosome 7q32. LCA12 (610612) is caused by mutation in the RD3 gene (180040) on chromosome 1q32. LCA13 (612712) is caused by mutation in the RDH12 gene (608830) on chromosome 14q24. LCA14 (613341) is caused by mutation in the LRAT gene (604863) on chromosome 4q32. LCA15 (613843) is caused by mutation in the TULP1 gene (602280) on chromosome 6p21. LCA16 (614186) is caused by mutation in the KCNJ13 gene (603208) on chromosome 2q37. LCA17 (615360) is caused by mutation in the GDF6 gene (601147) on chromosome 8q22. LCA18 (see 608133) is caused by mutation in the PRPH2 gene (179605) on chromosome 6p21. Perrault et al. (1999) provided a review of Leber congenital amaurosis, with emphasis on genetic heterogeneity. Wiszniewski et al. (2011) analyzed 13 known LCA genes in 60 LCA probands, and identified homozygous or compound heterozygous mutations in 42 (70%). In addition, a third disease-associated mutant allele at a second locus was identified in 7 (12%) of the 60 patients. Wiszniewski et al. (2011) stated that the significance of the third mutated allele was unknown, but suggested that mutational load might be important to penetrance of the LCA phenotype. Because LCA manifests very early in life and results in profound vision loss, patients with mutations in other syndromic or nonsyndromic eye disease genes may receive an initial diagnosis of LCA, prior to development of syndromic features or before more thorough phenotyping can be performed (see, e.g., Senior-Loken syndrome-5, 609254).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:128392779
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:128392779
Likely benign
Hetero
Gene:
KEL
Variant:
c.578C>T
(p.Thr193Met)
rsID: rs8176058
Ref Allele: G
Alt Allele: A
Freq: 2.73%uncommon
CADD: 17.87
ClinVar Submissions (1)
Last Evaluated: Jun 01, 1996
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 7:142957921
OMIM Allelic Variant: 613883.0001
Low clinical importance, Uncertain benign — This variant is also known as Kell or K1 or K (capitalized) in the Kell antigen system. K1-negative mothers (carrying no copies of this variant) carrying K1-positive fetuses (heterozygous or homozygous) are at risk for hemolytic disease of the newborn. About 9% of caucasians carry one or two copies of K1.
Benign
Hetero
Gene:
MGAT2
Variant:
c.*366C>G
rsID: rs1011373
Ref Allele: C
Alt Allele: G
Freq: 2.7451%uncommon
CADD: 16.23
ClinVar Submissions (1)
A genetically heterogeneous group of heritable disorders resulting from defects in protein N-glycosylation.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 14:49622978
Conflicting/Uncertain
Hetero
Gene:
SELENON
Variant:
c.981C>T
(p.Arg327=)
rsID: rs147587542
Ref Allele: C
Alt Allele: T
Freq: 2.7666%uncommon
CADD: 1.364
ClinVar Submissions (7)
Multiminicore disease (MmD) is broadly classified into four groups: Classic form (75% of individuals). Moderate form, with hand involvement (<10%). Antenatal form, with arthrogryposis multiplex congenita (<10%). Ophthalmoplegic form (<10%). Onset of the classic form is usually congenital or early in childhood with neonatal hypotonia, delayed motor development, axial muscle weakness, scoliosis, and significant respiratory involvement (often with secondary cardiac impairment). Spinal rigidity of varying severity is present.
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:25809791
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:25809791
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:25809791
Benign/Likely benign
Hetero
Gene:
COL18A1
Variant:
c.1455G>T
(p.Val485=)
rsID: rs17338853
Ref Allele: G
Alt Allele: T
Freq: 2.7746%uncommon
CADD: 3.082
ClinVar Submissions (2)
Knobloch syndrome is an autosomal recessive developmental disorder primarily characterized by typical eye abnormalities, including high myopia, cataracts, dislocated lens, vitreoretinal degeneration, and retinal detachment, with occipital skull defects, which can range from occipital encephalocele to occult cutis aplasia (summary by Aldahmesh et al., 2011).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 21:45476467
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 21:45476467
Benign/Likely benign
Hetero
Gene:
GAN
Variant:
c.*81T>C
rsID: rs78835723
Ref Allele: T
Alt Allele: C
Freq: 2.7873%uncommon
CADD: 4.722
ClinVar Submissions (1)
Giant axonal neuropathy (GAN) is an early-onset fatal neurodegenerative disorder. GAN starts as severe peripheral motor and sensory neuropathy during infancy and evolves into central nervous system impairment (intellectual disability, seizures, cerebellar signs, and pyramidal tract signs). Most individuals become wheelchair dependent in the second decade of life and eventually bedridden with severe polyneuropathy, ataxia, and dementia. Death usually occurs in the third decade.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 16:81377677
Likely benign
Hetero
Gene:
FANCA
Variant:
c.3348+18A>G
rsID: rs1800347
Ref Allele: T
Alt Allele: C
Freq: 2.7953%uncommon
CADD: 0.251
ClinVar Submissions (3)
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Oct 03, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 16:89748641
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Oct 03, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 16:89748641
Benign/Likely benign
Hetero
Gene:
MCFD2
Variant:
c.*1788C>T
rsID: rs115043642
Ref Allele: G
Alt Allele: A
Freq: 2.7969%uncommon
CADD: 4.308
ClinVar Submissions (1)
Combined deficiency of factor V (612309) and factor VIII (300841) is characterized by bleeding symptoms similar to those in hemophilia (306700) or parahemophilia (227400), caused by single deficiency of FV or FVIII, respectively. The most common symptoms are epistaxis, menorrhagia, and excessive bleeding during or after trauma. Plasma FV and FVIII antigen and activity levels are in the range of 5 to 30%. Inheritance of F5F8D is autosomal recessive and distinct from the coinheritance of FV deficiency and FVIII deficiency (summary by Zhang and Ginsburg, 2004). Genetic Heterogeneity of Combined Deficiency of Factor V and Factor VIII Another form of combined deficiency of factor V and factor VII (F5F8D2; 613625) is caused by mutation in the MCFD2 gene (607788) on chromosome 2.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 2:46903675
Conflicting/Uncertain
Hetero
Gene:
RNASEH2B
Variant:
c.-210G>C
rsID: rs112702177
Ref Allele: G
Alt Allele: C
Freq: 2.8232%uncommon
CADD: 9.053
ClinVar Submissions (1)
Most characteristically, Aicardi-Goutières syndrome (AGS) manifests as an early-onset encephalopathy that usually, but not always, results in severe intellectual and physical disability. A subgroup of infants with AGS present at birth with abnormal neurologic findings, hepatosplenomegaly, elevated liver enzymes, and thrombocytopenia, a picture highly suggestive of congenital infection. Otherwise, most affected infants present at variable times after the first few weeks of life, frequently after a period of apparently normal development. Typically, they demonstrate the subacute onset of a severe encephalopathy characterized by extreme irritability, intermittent sterile pyrexias, loss of skills, and slowing of head growth. Over time, as many as 40% develop chilblain skin lesions on the fingers, toes, and ears. It is becoming apparent that atypical, sometimes milder, cases of AGS exist, and thus the true extent of the phenotype associated with pathogenic variants in the AGS-related genes is not yet known.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 13:50909867
Likely benign
Hetero
Gene:
GRIN2A
Variant:
c.*1385C>A
rsID: rs113843373
Ref Allele: G
Alt Allele: T
Freq: 2.8614%uncommon
CADD: 0.895
ClinVar Submissions (1)
GRIN2A-related speech disorders and epilepsy are characterized by speech disorders in all affected individuals and a range of epilepsy syndromes present in about 90%. Severe speech disorders observed can include dysarthria and speech dyspraxia, and both receptive and expressive language delay/regression; more mildly affected individuals may display subtly impaired intelligibility of conversational speech. Epilepsy features include seizure onset usually between ages three and six years, focal epilepsy with language and/or global developmental regression, and electroencephalogram (EEG) showing continuous spike-and-wave discharges in sleep or very active centrotemporal discharges. Seizure types include seizures associated with aura of perioral paresthesia, focal or focal motor seizures (often evolving to generalized tonic-clonic), and atypical absence seizures. Epilepsy syndromes can include: Landau-Kleffner syndrome (LKS), epileptic encephalopathy with continuous spike-and-wave during sleep (ECSWS), childhood epilepsy with centrotemporal spikes (CECTS), atypical childhood epilepsy with centrotemporal spikes (ACECTS), autosomal dominant rolandic epilepsy with speech dyspraxia (ADRESD), and infantile-onset epileptic encephalopathy.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 16:9761764
Benign
Hetero
Gene:
CACNA1S
Variant:
c.3822C>T
(p.Ile1274=)
rsID: rs56183942
Ref Allele: G
Alt Allele: A
Freq: 2.8877%uncommon
CADD: 9.15
ClinVar Submissions (5)
Hypokalemic periodic paralysis (hypoPP) is a condition in which affected individuals may experience paralytic episodes with concomitant hypokalemia (serum potassium <3.5 mmol/L). The paralytic attacks are characterized by decreased muscle tone (flaccidity) more marked proximally than distally with normal to decreased deep tendon reflexes. The episodes develop over minutes to hours and last several minutes to several days with spontaneous recovery. Some individuals have only one episode in a lifetime; more commonly, crises occur repeatedly: daily, weekly, monthly, or less often. The major triggering factors are cessation of effort following strenuous exercise and carbohydrate-rich evening meals. Additional triggers can include cold, stress/excitement/fear, salt intake, prolonged immobility, use of glucosteroids or alcohol, and anesthetic procedures. The age of onset of the first attack ranges from two to 30 years; the duration of paralytic episodes ranges from one to 72 hours with an average of nearly 24 hours. Long-lasting interictal muscle weakness may occur in some affected individuals and in some stages of the disease and in myopathic muscle changes. A myopathy may occur independent of paralytic symptoms and may be the sole manifestation of hypoPP.
Last Evaluated: Oct 30, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:201053248
Hypokalemic periodic paralysis (hypoPP) is a condition in which affected individuals may experience paralytic episodes with concomitant hypokalemia (serum potassium <3.5 mmol/L). The paralytic attacks are characterized by decreased muscle tone (flaccidity) more marked proximally than distally with normal to decreased deep tendon reflexes. The episodes develop over minutes to hours and last several minutes to several days with spontaneous recovery. Some individuals have only one episode in a lifetime; more commonly, crises occur repeatedly: daily, weekly, monthly, or less often. The major triggering factors are cessation of effort following strenuous exercise and carbohydrate-rich evening meals. Additional triggers can include cold, stress/excitement/fear, salt intake, prolonged immobility, use of glucosteroids or alcohol, and anesthetic procedures. The age of onset of the first attack ranges from two to 30 years; the duration of paralytic episodes ranges from one to 72 hours with an average of nearly 24 hours. Long-lasting interictal muscle weakness may occur in some affected individuals and in some stages of the disease and in myopathic muscle changes. A myopathy may occur independent of paralytic symptoms and may be the sole manifestation of hypoPP.
Last Evaluated: Oct 30, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:201053248
Malignant hyperthermia susceptibility (MHS) is a pharmacogenetic disorder of skeletal muscle calcium regulation associated with uncontrolled skeletal muscle hypermetabolism. Manifestations of malignant hyperthermia (MH) are precipitated by certain volatile anesthetics (i.e., halothane, isoflurane, sevoflurane, desflurane, enflurane), either alone or in conjunction with a depolarizing muscle relaxant (specifically, succinylcholine). The triggering substances release calcium stores from the sarcoplasmic reticulum and may promote entry of calcium from the myoplasm, causing contracture of skeletal muscles, glycogenolysis, and increased cellular metabolism, resulting in production of heat and excess lactate. Affected individuals experience: acidosis, hypercapnia, tachycardia, hyperthermia, muscle rigidity, compartment syndrome, rhabdomyolysis with subsequent increase in serum creatine kinase (CK) concentration, hyperkalemia with a risk for cardiac arrhythmia or even arrest, and myoglobinuria with a risk for renal failure. In nearly all cases, the first manifestations of MH (tachycardia and tachypnea) occur in the operating room; however, MH may also occur in the early postoperative period. There is mounting evidence that some affected individuals will also develop MH with exercise and/or on exposure to hot environments. Without proper and prompt treatment with dantrolene sodium, mortality is extremely high.
Last Evaluated: Oct 30, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:201053248
Malignant hyperthermia susceptibility (MHS) is a pharmacogenetic disorder of skeletal muscle calcium regulation associated with uncontrolled skeletal muscle hypermetabolism. Manifestations of malignant hyperthermia (MH) are precipitated by certain volatile anesthetics (i.e., halothane, isoflurane, sevoflurane, desflurane, enflurane), either alone or in conjunction with a depolarizing muscle relaxant (specifically, succinylcholine). The triggering substances release calcium stores from the sarcoplasmic reticulum and may promote entry of calcium from the myoplasm, causing contracture of skeletal muscles, glycogenolysis, and increased cellular metabolism, resulting in production of heat and excess lactate. Affected individuals experience: acidosis, hypercapnia, tachycardia, hyperthermia, muscle rigidity, compartment syndrome, rhabdomyolysis with subsequent increase in serum creatine kinase (CK) concentration, hyperkalemia with a risk for cardiac arrhythmia or even arrest, and myoglobinuria with a risk for renal failure. In nearly all cases, the first manifestations of MH (tachycardia and tachypnea) occur in the operating room; however, MH may also occur in the early postoperative period. There is mounting evidence that some affected individuals will also develop MH with exercise and/or on exposure to hot environments. Without proper and prompt treatment with dantrolene sodium, mortality is extremely high.
Last Evaluated: Oct 30, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:201053248
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Oct 30, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:201053248
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Oct 30, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:201053248
Benign
Hetero
Gene:
MYH14
Variant:
c.474T>C
(p.Ile158=)
rsID: rs34796700
Ref Allele: T
Alt Allele: C
Freq: 2.9004%uncommon
CADD: 6.867
ClinVar Submissions (4)
Last Evaluated: Dec 06, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 19:50217683
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Dec 06, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 19:50217683
Benign/Likely benign
Hetero
Gene:
CASP10
Variant:
c.*815C>T
rsID: rs17860409
Ref Allele: C
Alt Allele: T
Freq: 2.9387%uncommon
CADD: 0.087
ClinVar Submissions (1)
Autoimmune lymphoproliferative syndrome (ALPS), caused by defective lymphocyte homeostasis, is characterized by the following: Non-malignant lymphoproliferation (lymphadenopathy, hepatosplenomegaly with or without hypersplenism) that often improves with age. Autoimmune disease, mostly directed toward blood cells. Lifelong increased risk for both Hodgkin and non-Hodgkin lymphoma. In ALPS-FAS (the most common and best-characterized type of ALPS, associated with heterozygous germline pathogenic variants in FAS), non-malignant lymphoproliferation typically manifests in the first years of life, inexplicably waxes and wanes, and then often decreases without treatment in the second decade of life; in many affected individuals, however, neither splenomegaly nor the overall expansion of lymphocyte subsets in peripheral blood decreases. Although autoimmunity is often not present at the time of diagnosis or at the time of the most extensive lymphoproliferation, autoantibodies can be detected before autoimmune disease manifests clinically. In ALPS-FAS caused by homozygous or compound heterozygous (biallelic) pathogenic variants in FAS, severe lymphoproliferation occurs before, at, or shortly after birth, and usually results in death at an early age. ALPS-sFAS, resulting from somatic FAS pathogenic variants in selected cell populations, notably the alpha/beta double-negative T cells (a/ß-DNT cells), appears to be similar to ALPS-FAS resulting from heterozygous germline pathogenic variants in FAS, although lower incidence of splenectomy and lower lymphocyte counts have been reported in ALPS-sFAS and no cases of lymphoma have yet been published.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:201218556
Likely benign
Hetero
Gene:
DIAPH1
Variant:
c.*1347C>G
rsID: rs251020
Ref Allele: G
Alt Allele: C
Freq: 2.953%uncommon
CADD: 9.03
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 5:141515504
Likely benign
Hetero
Gene:
NPHP3
Variant:
c.2571-7T>C
rsID: rs62292468
Ref Allele: A
Alt Allele: G
Freq: 2.9681%uncommon
CADD: 0.032
ClinVar Submissions (5)
A rare, lethal, autosomal recessive inherited syndrome characterized by pulmonary hypoplasia, central nervous system malformations, and hepatic malformations.
Last Evaluated: Aug 15, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:132690657
The nephronophthisis (NPH) phenotype is characterized by reduced renal concentrating ability, chronic tubulointerstitial nephritis, cystic renal disease, and progression to end-stage renal disease (ESRD) before age 30 years. Three age-based clinical subtypes are recongnized: infantile, juvenile, and adolescent/adult. Infantile NPH can present in utero with oligohydramnios sequence (limb contractures, pulmonary hypoplasia and facial dysmorphisms) or postnatally with renal manifestations that progress to ESRD before age 3 years. Juvenile NPH, the most prevalent subtype, typically presents with polydipsia and polyuria, growth retardation, chronic iron-resistant anemia, or other findings related to chronic kidney disease (CKD). Hypertension is typically absent due to salt wasting. ESRD develops at a median age of 13 years. Ultrasound findings are increased echogenicity, reduced corticomedullary differentiation, and renal cysts (in 50% of affected individuals). Histologic findings include tubulointerstitial fibrosis, thickened and disrupted tubular basement membrane, sporadic corticomedullary cysts, and normal or reduced kidney size. Adolescent/ adult NPH is clinically similar to juvenile NPH, but ESRD develops at a median age of 19 years. Within a subtype inter- and intrafamilial variability in rate of progression to ESRD is considerable. Approximately 80%-90% of individuals with the NPH phenotype have no extrarenal features (i.e., they have isolated NPH); ~10%-20% have extrarenal manifestations that constitute a recognizable syndrome (e.g., Joubert syndrome, Bardet-Biedl syndrome, Jeune syndrome and related skeletal disorders, Meckel-Gruber syndrome, Senior-Løken syndrome, Leber congenital amaurosis, COACH syndrome, and oculomotor apraxia, Cogan type).
Last Evaluated: Aug 15, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:132690657
Last Evaluated: Aug 15, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:132690657
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 15, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:132690657
Benign/Likely benign
Hetero
Gene:
TG
Variant:
c.5907G>A
(p.Pro1969=)
rsID: rs17693031
Ref Allele: G
Alt Allele: A
Freq: 2.9761%uncommon
CADD: 0.009
ClinVar Submissions (1)
A defect in any step of the biochemical pathway leading to production of thyroid hormones.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 8:132969501
Conflicting/Uncertain
Hetero
Gene:
HNRNPA2B1
Variant:
c.153+4T>C
rsID: rs41275982
Ref Allele: A
Alt Allele: G
Freq: 3.0334%uncommon
CADD: 8.523
ClinVar Submissions (2)
Last Evaluated: Aug 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 7:26197618
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 7:26197618
Benign
Hetero
Gene:
IGLL1
Variant:
c.475G>A
(p.Gly159Ser)
rsID: rs139571703
Ref Allele: C
Alt Allele: T
Freq: 3.0414%uncommon
CADD: 19.81
ClinVar Submissions (1)
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 22:23573433
Benign
Hetero
Gene:
ALAD
Variant:
c.*871C>A
rsID: rs8177822
Ref Allele: G
Alt Allele: T
Freq: 3.0693%uncommon
CADD: 1.188
ClinVar Submissions (1)
ALAD porphyria is a rare autosomal recessive disorder that has been reported and confirmed by genetic analysis in only 5 patients (Jaffe and Stith, 2007).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 9:113387429
Likely benign
Hetero
Gene:
FGFR3
Variant:
c.588C>T
(p.Arg196=)
rsID: rs2305180
Ref Allele: C
Alt Allele: T
Freq: 3.0804%uncommon
CADD: 2.831
ClinVar Submissions (4)
Last Evaluated: Jun 14, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 4:1801509
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 4:1801509
Benign
Hetero
Gene:
ERCC4
Variant:
c.974-7G>A
rsID: rs254942
Ref Allele: G
Alt Allele: A
Freq: 3.086%uncommon
CADD: 0.028
ClinVar Submissions (2)
Xeroderma pigmentosum (XP) is characterized by: Sun sensitivity (severe sunburn with blistering, persistent erythema on minimal sun exposure in ~60% of affected individuals), with marked freckle-like pigmentation of the face before age two years in most affected individuals; Sunlight-induced ocular involvement (photophobia, keratitis, atrophy of the skin of the lids); Greatly increased risk of sunlight-induced cutaneous neoplasms (basal cell carcinoma, squamous cell carcinoma, melanoma). Approximately 25% of affected individuals have neurologic manifestations (acquired microcephaly, diminished or absent deep tendon stretch reflexes, progressive sensorineural hearing loss, and progressive cognitive impairment). The most common causes of death are skin cancer, neurologic degeneration, and internal cancer. The median age at death in persons with XP with neurodegeneration (29 years) was found to be younger than that in persons with XP without neurodegeneration (37 years).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 16:13932150
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 16:13932150
Benign
Hetero
Gene:
PEX16
Variant:
c.-279G>A
rsID: rs2280330
Ref Allele: C
Alt Allele: T
Freq: 3.0892%uncommon
CADD: 8.698
ClinVar Submissions (1)
Zellweger spectrum disorder (ZSD) is a phenotypic continuum ranging from severe to mild. While individual phenotypes (e.g., Zellweger syndrome [ZS], neonatal adrenoleukodystrophy [NALD], and infantile Refsum disease [IRD]) were described in the past before the biochemical and molecular bases of this spectrum were fully determined, the term ZSD is now used to refer to all individuals with a PEX gene defect regardless of phenotype. Individuals with ZSD usually come to clinical attention in the newborn period or later in childhood. Affected newborns are hypotonic and feed poorly. They have distinctive facies, congenital malformations (neuronal migration defects associated with neonatal-onset seizures, renal cysts, and bony stippling [chondrodysplasia punctata] of the patella[e] and other long bones), and liver disease which can be severe. Infants with severe ZSD are significantly impaired and typically die during the first year of life, usually having made no developmental progress. Individuals with intermediate/milder ZSD do not have congenital malformations, but rather progressive peroxisome dysfunction variably manifest as sensory loss (secondary to retinal dystrophy and sensorineural hearing loss); neurologic involvement (ataxia, polyneuropathy, and leukodystrophy); liver dysfunction; adrenal insufficiency; and renal oxalate stones. While hypotonia and developmental delays are typical, intellect can be normal. Some have osteopenia; almost all have ameleogenesis imperfecta in the secondary teeth.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 11:45918090
Likely benign
Hetero
Gene:
EIF2B5
Variant:
c.*128T>C
rsID: rs14955
Ref Allele: T
Alt Allele: C
Freq: 3.1123%uncommon
CADD: 16
ClinVar Submissions (1)
Childhood ataxia with central nervous system hypomyelination/vanishing white matter disease (CACH/VWM) is characterized by ataxia, spasticity, and variable optic atrophy. The phenotypic range includes a prenatal/congenital form, a subacute infantile form (onset age <1 year), an early childhood onset form (onset age 1-5 years), a late childhood /juvenile onset form (onset age 5-15 years), and an adult onset form. The prenatal/congenital form is characterized by severe encephalopathy. In the later onset forms initial motor and intellectual development is normal or mildly delayed followed by neurologic deterioration with a chronic progressive or subacute course. Chronic progressive decline can be exacerbated by rapid deterioration during febrile illnesses or following head trauma or major surgical procedures, or by acute psychological stresses such as extreme fright.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 3:184145071
Likely benign
Hetero
Gene:
THAP1
Variant:
c.*686A>G
rsID: rs11557527
Ref Allele: T
Alt Allele: C
Freq: 3.1561%uncommon
CADD: 6.297
ClinVar Submissions (1)
An abnormally increased muscular tone that causes fixed abnormal postures. There is a slow, intermittent twisting motion that leads to exaggerated turning and posture of the extremities and trunk.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 8:42837276
Likely benign
Hetero
Gene:
SLC26A3
Variant:
c.921T>G
(p.Cys307Trp)
rsID: rs34407351
Ref Allele: A
Alt Allele: C
Freq: 3.1712%uncommon
CADD: 22.4
ClinVar Submissions (1)
Congenital secretory chloride diarrhea is an autosomal recessive form of severe chronic diarrhea characterized by excretion of large amounts of watery stool containing high levels of chloride, resulting in dehydration, hypokalemia, and metabolic alkalosis. The electrolyte disorder resembles the renal disorder Bartter syndrome (see 607364), except that chloride diarrhea is not associated with calcium level abnormalities (summary by Choi et al., 2009). Genetic Heterogeneity of Diarrhea Other forms of diarrhea include DIAR2 (251850), caused by mutation in the MYO5B gene (606540) on 18q21; DIAR3 (270420), caused by mutation in the SPINT2 gene (605124) on 19q13; DIAR4 (610370), caused by mutation in the NEUROG3 gene (604882) on 10q21; DIAR5 (613217), caused by mutation in the EPCAM gene (185535) on 2p21; DIAR6 (614616), caused by mutation in the GUCY2C gene (601330) on 12p12; DIAR7 (615863) caused by mutation in the DGAT1 gene (604900) on 8q24; DIAR8 (616868), caused by mutation in the SLC9A3 gene (182307) on 5p15; DIAR9 (618168), caused by mutation in the WNT2B gene (601968) on 1p13; and DIAR10 (618183), caused by mutation in the PLVAP gene (607647) on 19p13.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:107786877
Likely benign
Hetero
Gene:
NOTCH3
Variant:
c.*563T>C
rsID: rs77669983
Ref Allele: A
Alt Allele: G
Freq: 3.1863%uncommon
CADD: 11.96
ClinVar Submissions (1)
CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is characterized by mid-adult onset of recurrent ischemic stroke, cognitive decline progressing to dementia, a history of migraine with aura, mood disturbance, apathy, and diffuse white matter lesions and subcortical infarcts on neuroimaging.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 19:15160099
Likely benign
Hetero
Gene:
TNFRSF13B
Variant:
c.291T>G
(p.Pro97=)
rsID: rs35062843
Ref Allele: A
Alt Allele: C
Freq: 3.2054%uncommon
CADD: 8.492
ClinVar Submissions (5)
Last Evaluated: Jul 31, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:16948892
Common variable immune deficiency (CVID) is a disorder that impairs the immune system. People with CVID are highly susceptible to infection from foreign invaders such as bacteria, or more rarely, viruses and often develop recurrent infections, particularly in the lungs, sinuses, and ears. Pneumonia is common in people with CVID. Over time, recurrent infections can lead to chronic lung disease. Affected individuals may also experience infection or inflammation of the gastrointestinal tract, which can cause diarrhea and weight loss. Abnormal accumulation of immune cells causes enlarged lymph nodes (lymphadenopathy) or an enlarged spleen (splenomegaly) in some people with CVID. Immune cells can accumulate in other organs, forming small lumps called granulomas.Approximately 25 percent of people with CVID have an autoimmune disorder, which occurs when the immune system malfunctions and attacks the body's tissues and organs. The blood cells are most frequently affected by autoimmune attacks in CVID; the most commonly occurring autoimmune disorders are immune thrombocytopenia, which is an abnormal bleeding disorder caused by a decrease in cell fragments involved in blood clotting called platelets, and autoimmune hemolytic anemia, which results in premature destruction of red blood cells. Other autoimmune disorders such as rheumatoid arthritis can occur. Individuals with CVID also have a greater than normal risk of developing certain types of cancer, including a cancer of immune system cells called non-Hodgkin lymphoma and less frequently, stomach (gastric) cancer.People with CVID may start experiencing signs and symptoms of the disorder anytime between childhood and adulthood; most people with CVID are diagnosed in their twenties or thirties. The life expectancy of individuals with CVID varies depending on the severity and frequency of illnesses they experience. Most people with CVID live into adulthood.There are many different types of CVID that are distinguished by genetic cause. People with the same type of CVID may have varying signs and symptoms.
Last Evaluated: Jul 31, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:16948892
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jul 31, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:16948892
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 31, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:16948892
Benign/Likely benign
Hetero
Gene:
SALL1
Variant:
c.*997C>A
rsID: rs116971887
Ref Allele: G
Alt Allele: T
Freq: 3.2325%uncommon
CADD: 17.33
ClinVar Submissions (1)
Townes-Brocks syndrome (TBS) is characterized by the triad of imperforate anus (84%), dysplastic ears (87%; overfolded superior helices and preauricular tags; frequently associated with sensorineural and/or conductive hearing impairment [65%]), and thumb malformations (89%; triphalangeal thumbs, duplication of the thumb [preaxial polydactyly], and rarely hypoplasia of the thumbs). Renal impairment (42%), including end-stage renal disease (ESRD), may occur with or without structural abnormalities (mild malrotation, ectopia, horseshoe kidney, renal hypoplasia, polycystic kidneys, vesicoutereral reflux). Congenital heart disease occurs in 25%. Foot malformations (52%; flat feet, overlapping toes) and genitourinary malformations (36%) are common. Intellectual disability occurs in approximately 10% of individuals. Rare features include iris coloboma, Duane anomaly, Arnold-Chiari malformation type 1, and growth retardation.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 16:51136115
Benign
Hetero
Gene:
CTNS
Variant:
c.970+15G>A
rsID: rs76153698
Ref Allele: G
Alt Allele: A
Freq: 3.2381%uncommon
CADD: 0.017
ClinVar Submissions (4)
Cystinosis comprises three allelic phenotypes: Nephropathic cystinosis in untreated children is characterized by renal Fanconi syndrome, poor growth, hypophosphatemic/calcipenic rickets, impaired glomerular function resulting in complete glomerular failure, and accumulation of cystine in almost all cells, leading to cellular dysfunction with tissue and organ impairment. The typical untreated child has short stature, rickets, and photophobia. Failure to thrive is generally noticed after approximately age six months; signs of renal tubular Fanconi syndrome (polyuria, polydipsia, dehydration, and acidosis) appear as early as age six months; corneal crystals can be present before age one year and are always present after age 16 months. Prior to the use of renal transplantation and cystine-depleting therapy, the life span in nephropathic cystinosis was no longer than ten years. With these interventions, affected individuals can survive at least into the mid-forties or fifties with satisfactory quality of life. Intermediate cystinosis is characterized by all the typical manifestations of nephropathic cystinosis, but onset is at a later age. Renal glomerular failure occurs in all untreated affected individuals, usually between ages 15 and 25 years. The non-nephropathic (ocular) form of cystinosis is characterized clinically only by photophobia resulting from corneal cystine crystal accumulation.
Last Evaluated: Jun 05, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:3659990
Last Evaluated: Jun 05, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:3659990
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jun 05, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:3659990
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 05, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:3659990
Benign/Likely benign
Hetero
Gene:
PCSK1
Variant:
c.661A>G
(p.Asn221Asp)
rsID: rs6232
Ref Allele: T
Alt Allele: C
Freq: 3.2429%uncommon
CADD: 22.8
ClinVar Submissions (2)
Last Evaluated: Jan 18, 2018
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 5:96416081
OMIM Allelic Variant: 162150.0005
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jan 18, 2018
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 5:96416081
OMIM Allelic Variant: 162150.0005
Benign
Hetero
Gene:
IL10RA
Variant:
c.1259C>T
(p.Ser420Leu)
rsID: rs2229114
Ref Allele: C
Alt Allele: T
Freq: 3.2437%uncommon
CADD: 8.978
ClinVar Submissions (2)
A spectrum of small and large bowel inflammatory diseases of unknown etiology. It includes Crohn's disease, ulcerative colitis, and colitis of indeterminate type.
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:117999163
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:117999163
Benign/Likely benign
Hetero
Gene:
CDK4
Variant:
c.*521G>A
rsID: rs113625101
Ref Allele: C
Alt Allele: T
Freq: 3.3018%uncommon
CADD: 2.032
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 12:57748004
Likely benign
Hetero
Gene:
RHBDF2
Variant:
c.*511G>A
rsID: rs11553544
Ref Allele: C
Alt Allele: T
Freq: 3.3122%uncommon
CADD: 3.187
ClinVar Submissions (1)
Palmoplantar keratoderma (PPK) is a complex group of hereditary syndromes that have been classified into diffuse, punctate, and focal forms according to the pattern of hyperkeratosis on the palms and soles (Lucker et al., 1994). For a discussion of phenotypic and genetic heterogeneity of palmoplantar keratoderma, see epidermolytic PPK (144200).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 17:76471122
Likely benign
Hetero
Gene:
LEP
Variant:
c.*366A>T
rsID: rs28954118
Ref Allele: A
Alt Allele: T
Freq: 3.3408%uncommon
CADD: 2.092
ClinVar Submissions (1)
Congenital leptin deficiency is a condition that causes severe obesity beginning in the first few months of life. Affected individuals are of normal weight at birth, but they are constantly hungry and quickly gain weight. Without treatment, the extreme hunger continues and leads to chronic excessive eating (hyperphagia) and obesity. Beginning in early childhood, affected individuals develop abnormal eating behaviors such as fighting with other children over food, hoarding food, and eating in secret.People with congenital leptin deficiency also have hypogonadotropic hypogonadism, which is a condition caused by reduced production of hormones that direct sexual development. Without treatment, affected individuals experience delayed puberty or do not go through puberty, and may be unable to conceive children (infertile).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 7:128255129
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 7:128255129
Conflicting/Uncertain
Hetero
Gene:
CTNS
Variant:
c.*2115G>A
rsID: rs77196744
Ref Allele: G
Alt Allele: A
Freq: 3.348%uncommon
CADD: 0.001
ClinVar Submissions (1)
Cystinosis comprises three allelic phenotypes: Nephropathic cystinosis in untreated children is characterized by renal Fanconi syndrome, poor growth, hypophosphatemic/calcipenic rickets, impaired glomerular function resulting in complete glomerular failure, and accumulation of cystine in almost all cells, leading to cellular dysfunction with tissue and organ impairment. The typical untreated child has short stature, rickets, and photophobia. Failure to thrive is generally noticed after approximately age six months; signs of renal tubular Fanconi syndrome (polyuria, polydipsia, dehydration, and acidosis) appear as early as age six months; corneal crystals can be present before age one year and are always present after age 16 months. Prior to the use of renal transplantation and cystine-depleting therapy, the life span in nephropathic cystinosis was no longer than ten years. With these interventions, affected individuals can survive at least into the mid-forties or fifties with satisfactory quality of life. Intermediate cystinosis is characterized by all the typical manifestations of nephropathic cystinosis, but onset is at a later age. Renal glomerular failure occurs in all untreated affected individuals, usually between ages 15 and 25 years. The non-nephropathic (ocular) form of cystinosis is characterized clinically only by photophobia resulting from corneal cystine crystal accumulation.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 17:3662484
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 17:3662484
Likely benign
Hetero
Gene:
COL9A2
Variant:
c.1288-12C>T
rsID: rs77695700
Ref Allele: G
Alt Allele: A
Freq: 3.3575%uncommon
CADD: 0.076
ClinVar Submissions (4)
Autosomal dominant multiple epiphyseal dysplasia (MED) presents in early childhood, usually with pain in the hips and/or knees after exercise. Affected children complain of fatigue with long-distance walking. Waddling gait may be present. Adult height is either in the lower range of normal or mildly shortened. The limbs are relatively short in comparison to the trunk. Pain and joint deformity progress, resulting in early-onset osteoarthritis, particularly of the large weight-bearing joints.
Last Evaluated: Oct 25, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:40304111
Last Evaluated: Oct 25, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:40304111
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Oct 25, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:40304111
Benign/Likely benign
Hetero
Gene:
SMAD9
Variant:
c.-258T>C
rsID: rs575906743
Ref Allele: A
Alt Allele: G
Freq: 3.4013%uncommon
CADD: 18.19
ClinVar Submissions (1)
Pulmonary arterial hypertension (PAH) is characterized by widespread obstruction and obliteration of the smallest pulmonary arteries. When a sufficient number of vessels are occluded, the resistance to blood flow through the lungs increases, and the right ventricle attempts to compensate by generating higher pressure to maintain pulmonary blood flow. When the right ventricle can no longer compensate for the increased resistance, progressive heart failure ensues. Initial symptoms include dyspnea (60%), fatigue (19%), syncope (8%), chest pain (7%), palpitations (5%), and leg edema (3%). All ages are affected, but the mean age at diagnosis is 36 years. Mean survival after diagnosis is 2.8 years; current therapy does improve clinical function but has modest effect on survival. The term "heritable PAH" (HPAH) includes familial PAH (PAH that occurs in two or more family members) and simplex PAH (i.e., a single occurrence in a family) when a pathogenic variant has been identified. Most heritable PAH (75%) is caused by a pathogenic variant in BMPR2; pathogenic variants in other genes (i.e., ACVRL1, KCNK3, CAV1, SMAD9, BMPR1B) are considerably less common (1%-3%). HPAH has identical symptoms, signs, and histology as PAH of unknown cause. The time from onset of symptoms to diagnosis may be shorter in individuals with familial PAH, possibly because of familial awareness of the disease. Three retrospective studies suggest that persons with PAH who have a BMPR2 pathogenic variant exhibit more severe disease.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 13:36920187
Benign
Hetero
Gene:
GRIN2A
Variant:
c.*2017C>G
rsID: rs112151383
Ref Allele: G
Alt Allele: C
Freq: 3.4077%uncommon
CADD: 0.27
ClinVar Submissions (1)
GRIN2A-related speech disorders and epilepsy are characterized by speech disorders in all affected individuals and a range of epilepsy syndromes present in about 90%. Severe speech disorders observed can include dysarthria and speech dyspraxia, and both receptive and expressive language delay/regression; more mildly affected individuals may display subtly impaired intelligibility of conversational speech. Epilepsy features include seizure onset usually between ages three and six years, focal epilepsy with language and/or global developmental regression, and electroencephalogram (EEG) showing continuous spike-and-wave discharges in sleep or very active centrotemporal discharges. Seizure types include seizures associated with aura of perioral paresthesia, focal or focal motor seizures (often evolving to generalized tonic-clonic), and atypical absence seizures. Epilepsy syndromes can include: Landau-Kleffner syndrome (LKS), epileptic encephalopathy with continuous spike-and-wave during sleep (ECSWS), childhood epilepsy with centrotemporal spikes (CECTS), atypical childhood epilepsy with centrotemporal spikes (ACECTS), autosomal dominant rolandic epilepsy with speech dyspraxia (ADRESD), and infantile-onset epileptic encephalopathy.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 16:9761132
Benign
Hetero
Gene:
MDN1
Variant:
c.14159T>C
(p.Ile4720Thr)
rsID: rs16882046
Ref Allele: A
Alt Allele: G
Freq: 3.438%uncommon
CADD: 21
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 29, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 6:89664564
Benign
Hetero
Gene:
MDN1
Variant:
c.12796A>G
(p.Arg4266Gly)
rsID: rs41273327
Ref Allele: T
Alt Allele: C
Freq: 3.4603%uncommon
CADD: 17.49
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 29, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 6:89674555
Benign
Hetero
Gene:
NDUFAF4
Variant:
c.*387C>T
rsID: rs41288596
Ref Allele: G
Alt Allele: A
Freq: 3.4786%uncommon
CADD: 0.994
ClinVar Submissions (1)
Isolated complex I deficiency is the most common enzymatic defect of the oxidative phosphorylation disorders (McFarland et al., 2004; Kirby et al., 2004). It causes a wide range of clinical disorders, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, nonspecific encephalopathy, hypertrophic cardiomyopathy, myopathy, liver disease, Leigh syndrome (see 256000), Leber hereditary optic neuropathy (535000), and some forms of Parkinson disease (see 556500) (Loeffen et al., 2000; Pitkanen et al., 1996; Robinson, 1998). Genetic Heterogeneity of Complex I Deficiency Mitochondrial complex I deficiency shows extreme genetic heterogeneity and can be caused by mutation in nuclear-encoded genes or in mitochondrial-encoded genes. There are no obvious genotype-phenotype correlations, and inference of the underlying basis from the clinical or biochemical presentation is difficult, if not impossible (summary by Haack et al., 2012). However, the majority of cases are caused by mutations in nuclear-encoded genes (Loeffen et al., 2000; Triepels et al., 2001). Complex I deficiency resulting from mutation in nuclear-encoded genes include MC1DN1, caused by mutation in the NDUFS4 gene (602694); MC1DN2 (618222), caused by mutation in the NDUFS8 gene (602141); MC1DN3 (618224), caused by mutation in the NDUFS7 gene (601825); MC1DN4 (618225), caused by mutation in the NDUFV1 gene (161015); MC1DN5 (618226), caused by mutation in the NDUFS1 gene (157655); MC1DN6 (618228), caused by mutation in the NDUFS2 gene (602985); MC1DN7 (618229), caused by mutation in the NDUFV2 gene (600532); MC1DN8 (618230), caused by mutation in the NDUFS3 gene (603846); MC1DN9 (618232), caused by mutation in the NDUFS6 gene (603848); MC1DN10 (618233), caused by mutation in the NDUFAF2 gene (609653); MC1DN11 (618234), caused by mutation in the NDUFAF1 gene (606934); MC1DN12 (301020), caused by mutation in the NDUFA1 gene (300078); MC1DN13 (618235), caused by mutation in the NDUFA2 gene (602137); MC1DN14 (618236), caused by mutation in the NDUFA11 gene (612638); MC1DN15 (618237), caused by mutation in the NDUFAF4 gene (611776); MC1DN16 (618238), caused by mutation in the NDUFAF5 gene (612360); MC1DN17 (618239), caused by mutation in the NDUFAF6 gene (612392); MC1DN18 (618240), caused by mutation in the NDUFAF3 gene (612911); MC1DN19 (618241), caused by mutation in the FOXRED1 gene (613622); MC1DN20 (611126), caused by mutation in the ACAD9 gene (611103); MC1DN21 (618242), caused by mutation in the NUBPL gene (613621); MC1DN22 (618243), caused by mutation in the NDUFA10 gene (603835); MC1DN23 (618244), caused by mutation in the NDUFA12 gene (614530); MC1DN24 (618245), caused by mutation in the NDUFB9 gene (601445); MC1DN25 (618246), caused by mutation in the NDUFB3 gene (603839); MC1DN26 (618247), caused by mutation in the NDUFA9 gene (603834); MC1DN27 (618248), caused by mutation in the MTFMT gene (611766); MC1DN28 (618249), caused by mutation in the NDUFA13 gene (609435); MC1DN29 (618250), caused by mutation in the TMEM126B gene (615533); MC1DN30 (301021), caused by mutation in the NDUFB11 gene (300403); MC1DN31 (618251), caused by mutation in the TIMMDC1 gene (615534); MC1DN32 (618252), caused by mutation in the NDUFB8 gene (602140); and MC1DN33 (618253), caused by mutation in the NDUFA6 gene (602138). Complex I deficiency with mitochondrial inheritance has been associated with mutation in 6 mitochondrial-encoded components of complex I: MTND1 (516000), MTND2 (516001), MTND3 (516002), MTND4 (516003), MTND5 (516005), MTND6 (516006). Most of these patients have a phenotype of Leber hereditary optic neuropathy (LHON; 535000) or Leigh syndrome. Features of complex I deficiency may also be caused by mutation in other mitochondrial genes, including MTTS2 (590085).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 6:96890717
Conflicting/Uncertain
Hetero
Gene:
TNPO3
Variant:
c.2205C>T
(p.Leu735=)
rsID: rs2293493
Ref Allele: G
Alt Allele: A
Freq: 3.5057%uncommon
CADD: 14.04
ClinVar Submissions (2)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Feb 26, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 7:128974936
Benign
Hetero
Gene:
CASP10
Variant:
c.*1520C>T
rsID: rs41331447
Ref Allele: C
Alt Allele: T
Freq: 3.5256%uncommon
CADD: 2.697
ClinVar Submissions (1)
Autoimmune lymphoproliferative syndrome (ALPS), caused by defective lymphocyte homeostasis, is characterized by the following: Non-malignant lymphoproliferation (lymphadenopathy, hepatosplenomegaly with or without hypersplenism) that often improves with age. Autoimmune disease, mostly directed toward blood cells. Lifelong increased risk for both Hodgkin and non-Hodgkin lymphoma. In ALPS-FAS (the most common and best-characterized type of ALPS, associated with heterozygous germline pathogenic variants in FAS), non-malignant lymphoproliferation typically manifests in the first years of life, inexplicably waxes and wanes, and then often decreases without treatment in the second decade of life; in many affected individuals, however, neither splenomegaly nor the overall expansion of lymphocyte subsets in peripheral blood decreases. Although autoimmunity is often not present at the time of diagnosis or at the time of the most extensive lymphoproliferation, autoantibodies can be detected before autoimmune disease manifests clinically. In ALPS-FAS caused by homozygous or compound heterozygous (biallelic) pathogenic variants in FAS, severe lymphoproliferation occurs before, at, or shortly after birth, and usually results in death at an early age. ALPS-sFAS, resulting from somatic FAS pathogenic variants in selected cell populations, notably the alpha/beta double-negative T cells (a/ß-DNT cells), appears to be similar to ALPS-FAS resulting from heterozygous germline pathogenic variants in FAS, although lower incidence of splenectomy and lower lymphocyte counts have been reported in ALPS-sFAS and no cases of lymphoma have yet been published.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:201219261
Likely benign
Hetero
Gene:
SBDS
Variant:
c.651C>T
(p.Phe217=)
rsID: rs73151675
Ref Allele: G
Alt Allele: A
Freq: 3.5415%uncommon
CADD: 11.22
ClinVar Submissions (4)
Shwachman-Diamond syndrome (SDS) is characterized by: exocrine pancreatic dysfunction with malabsorption, malnutrition, and growth failure; hematologic abnormalities with single- or multilineage cytopenias and susceptibility to myelodysplasia syndrome (MDS) and acute myelogeneous leukemia (AML); and bone abnormalities. In almost all affected children, persistent or intermittent neutropenia is a common presenting finding, often before the diagnosis of SDS is made. Short stature and recurrent infections are common.
Last Evaluated: Mar 29, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 7:66988473
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 29, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 7:66988473
Benign
Hetero
Gene:
KRT85
Variant:
c.233G>A
(p.Arg78His)
rsID: rs61630004
Ref Allele: C
Alt Allele: T
Freq: 3.6012%uncommon
CADD: 17.51
ClinVar Submissions (3)
Some ectodermal dysplasias are here classified as congenital disorders characterized by abnormal development in 2 or more ectodermal structures (hair, nails, teeth, and sweat glands) without other systemic findings. Ectodermal dysplasia of the hair/nail type is a rare congenital condition characterized by hypotrichosis and nail dystrophy without nonectodermal or other ectodermal manifestations.
Last Evaluated: Mar 28, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 12:52367173
OMIM Allelic Variant: 602767.0001
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Mar 28, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 12:52367173
OMIM Allelic Variant: 602767.0001
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Mar 28, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 12:52367173
OMIM Allelic Variant: 602767.0001
Low clinical importance, Uncertain benign — Presumed benign. Although this variant was implicated in causing ectodermal dysplasia in a recessive manner in two Pakistani families (one of which was large and consanguineous), GET-Evidence reports that the variant has been seen in 5 out of 114 random control chromosomes. This strongly contradicts a severe pathogenic effect.
Clinically Significant Benign
Hetero
Gene:
PIGO
Variant:
c.3114C>T
(p.Leu1038=)
rsID: rs2298314
Ref Allele: G
Alt Allele: A
Freq: 3.6387%uncommon
CADD: 10.28
ClinVar Submissions (5)
Hyperphosphatasia with mental retardation syndrome-2 is an autosomal recessive disorder characterized by moderately to severely delayed psychomotor development, facial dysmorphism, brachytelephalangy, and increased serum alkaline phosphatase (hyperphosphatasia). Some patients may have additional features, such as cardiac septal defects or seizures (summary by Krawitz et al., 2012). The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis. For a discussion of genetic heterogeneity of hyperphosphatasia with mental retardation syndrome, see HPMRS1 (239300). For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).
Last Evaluated: Aug 01, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 9:35089406
Mabry syndrome is a condition characterized by intellectual disability, distinctive facial features, increased levels of an enzyme called alkaline phosphatase in the blood (hyperphosphatasia), and other signs and symptoms.People with Mabry syndrome have intellectual disability that is often moderate to severe. They typically have little to no speech development and are delayed in the development of motor skills (such as sitting, crawling, and walking). Many affected individuals have low muscle tone (hypotonia) and develop recurrent seizures (epilepsy) in early childhood. Seizures are usually the generalized tonic-clonic type, which involve muscle rigidity, convulsions, and loss of consciousness.Individuals with Mabry syndrome have distinctive facial features that include wide-set eyes (hypertelorism), long openings of the eyelids (long palpebral fissures), a nose with a broad bridge and a rounded tip, downturned corners of the mouth, and a thin upper lip. These facial features usually become less pronounced over time.Hyperphosphatasia begins within the first year of life in people with Mabry syndrome. There are many different types of alkaline phosphatase found in tissues; the type that is increased in Mabry syndrome is called the tissue non-specific type and is found throughout the body. In affected individuals, alkaline phosphatase levels in the blood are usually increased by one to two times the normal amount, but can be up to 20 times higher than normal. The elevated enzyme levels remain relatively stable over a person's lifetime. Hyperphosphatasia appears to cause no negative health effects, but this finding can help health professionals diagnose Mabry syndrome.Another common feature of Mabry syndrome is shortened bones at the ends of fingers (brachytelephalangy), which can be seen on x-ray imaging. Underdeveloped fingernails (nail hypoplasia) may also occur. Sometimes, individuals with Mabry syndrome have abnormalities of the digestive system, including narrowing or blockage of the anus (anal stenosis or anal atresia) or Hirschsprung disease, a disorder that causes severe constipation or blockage of the intestine. Rarely, affected individuals experience hearing loss.The signs and symptoms of Mabry syndrome vary among affected individuals. Those who are least severely affected have only intellectual disability and hyperphosphatasia, without distinctive facial features or the other health problems listed above.
Last Evaluated: Aug 01, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 9:35089406
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 01, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 9:35089406
Benign
Hetero
Gene:
NTRK1
Variant:
c.1810C>T
(p.His604Tyr)
rsID: rs6336
Ref Allele: C
Alt Allele: T
Freq: 3.6411%uncommon
CADD: 26.2
ClinVar Submissions (6)
Multiple endocrine neoplasia type 2 (MEN 2) is classified into three subtypes: MEN 2A, FMTC (familial medullary thyroid carcinoma), and MEN 2B. All three subtypes involve high risk for development of medullary carcinoma of the thyroid (MTC); MEN 2A and MEN 2B have an increased risk for pheochromocytoma; MEN 2A has an increased risk for parathyroid adenoma or hyperplasia. Additional features in MEN 2B include mucosal neuromas of the lips and tongue, distinctive facies with enlarged lips, ganglioneuromatosis of the gastrointestinal tract, and a "marfanoid" habitus. MTC typically occurs in early childhood in MEN 2B, early adulthood in MEN 2A, and middle age in FMTC.
Last Evaluated: Oct 05, 2017
Review Status: no interpretation for the single variant
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 1:156879126
OMIM Allelic Variant: 191315.0005
Congenital insensitivity to pain with anhidrosis (CIPA), also known as hereditary sensory and autonomic neuropathy type IV (HSAN IV), is characterized by insensitivity to pain, anhidrosis (the inability to sweat), and intellectual disability. The ability to sense all pain (including visceral pain) is absent, resulting in repeated injuries including: oral self-mutilation (biting of tongue, lips, and buccal mucosa); biting of fingertips; bruising, scarring, and infection of the skin; multiple bone fractures (many of which fail to heal properly); and recurrent joint dislocations resulting in joint deformity. Sense of touch, vibration, and position are normal. Anhidrosis predisposes to recurrent febrile episodes that are often the initial manifestation of CIPA. Hypothermia in cold environments also occurs. Intellectual disability of varying degree is observed in most affected individuals; hyperactivity and emotional lability are common.
Last Evaluated: Oct 05, 2017
Review Status: no interpretation for the single variant
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 1:156879126
OMIM Allelic Variant: 191315.0005
Congenital insensitivity to pain with anhidrosis (CIPA), also known as hereditary sensory and autonomic neuropathy type IV (HSAN IV), is characterized by insensitivity to pain, anhidrosis (the inability to sweat), and intellectual disability. The ability to sense all pain (including visceral pain) is absent, resulting in repeated injuries including: oral self-mutilation (biting of tongue, lips, and buccal mucosa); biting of fingertips; bruising, scarring, and infection of the skin; multiple bone fractures (many of which fail to heal properly); and recurrent joint dislocations resulting in joint deformity. Sense of touch, vibration, and position are normal. Anhidrosis predisposes to recurrent febrile episodes that are often the initial manifestation of CIPA. Hypothermia in cold environments also occurs. Intellectual disability of varying degree is observed in most affected individuals; hyperactivity and emotional lability are common.
Last Evaluated: Oct 05, 2017
Review Status: no interpretation for the single variant
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 1:156879126
OMIM Allelic Variant: 191315.0005
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Oct 05, 2017
Review Status: no interpretation for the single variant
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 1:156879126
OMIM Allelic Variant: 191315.0005
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Oct 05, 2017
Review Status: no interpretation for the single variant
Number of Submitters: 6
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 1:156879126
OMIM Allelic Variant: 191315.0005
Low clinical importance, Uncertain benign — Various databases and papers treat this variant as a non-pathogenic polymorphism, although it is fairly uncommon and is computational methods predict it to be damaging.
Clinically Significant Conflicting/Uncertain
Hetero
Gene:
CYP1B1
Variant:
c.*1871C>T
rsID: rs9341266
Ref Allele: G
Alt Allele: A
Freq: 3.6442%uncommon
CADD: 8.911
ClinVar Submissions (1)
Anterior segment dysgeneses (ASGD or ASMD) are a heterogeneous group of developmental disorders affecting the anterior segment of the eye, including the cornea, iris, lens, trabecular meshwork, and Schlemm canal. The clinical features of ASGD include iris hypoplasia, an enlarged or reduced corneal diameter, corneal vascularization and opacity, posterior embryotoxon, corectopia, polycoria, an abnormal iridocorneal angle, ectopia lentis, and anterior synechiae between the iris and posterior corneal surface (summary by Cheong et al., 2016). Anterior segment dysgenesis is sometimes divided into subtypes including aniridia (see 106210), Axenfeld and Rieger anomalies, iridogoniodysgenesis, Peters anomaly, and posterior embryotoxon (Gould and John, 2002). Patients with ASGD5 have been reported with the Peters anomaly, Axenfeld anomaly, and Rieger anomaly subtypes. Peters anomaly consists of a central corneal leukoma, absence of the posterior corneal stroma and Descemet membrane, and a variable degree of iris and lenticular attachments to the central aspect of the posterior cornea (Peters, 1906). It occurs as an isolated ocular abnormality or in association with other ocular defects. In Axenfeld anomaly, strands of iris tissue attach to the Schwalbe line; in Rieger anomaly, in addition to the attachment of iris tissue to the Schwalbe line, there is clinically evident iris stromal atrophy with hole or pseudo-hole formation and corectopia (summary by Smith and Traboulsi, 2012).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:38068851
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:38068851
Likely benign
Hetero
Gene:
NTRK1
Variant:
c.1730G>T
(p.Gly577Val)
rsID: rs6339
Ref Allele: G
Alt Allele: T
Freq: 3.645%uncommon
CADD: 22.1
ClinVar Submissions (7)
Multiple endocrine neoplasia type 2 (MEN 2) is classified into three subtypes: MEN 2A, FMTC (familial medullary thyroid carcinoma), and MEN 2B. All three subtypes involve high risk for development of medullary carcinoma of the thyroid (MTC); MEN 2A and MEN 2B have an increased risk for pheochromocytoma; MEN 2A has an increased risk for parathyroid adenoma or hyperplasia. Additional features in MEN 2B include mucosal neuromas of the lips and tongue, distinctive facies with enlarged lips, ganglioneuromatosis of the gastrointestinal tract, and a "marfanoid" habitus. MTC typically occurs in early childhood in MEN 2B, early adulthood in MEN 2A, and middle age in FMTC.
Last Evaluated: Oct 05, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 1:156879154
OMIM Allelic Variant: 191315.0005
Congenital insensitivity to pain with anhidrosis (CIPA), also known as hereditary sensory and autonomic neuropathy type IV (HSAN IV), is characterized by insensitivity to pain, anhidrosis (the inability to sweat), and intellectual disability. The ability to sense all pain (including visceral pain) is absent, resulting in repeated injuries including: oral self-mutilation (biting of tongue, lips, and buccal mucosa); biting of fingertips; bruising, scarring, and infection of the skin; multiple bone fractures (many of which fail to heal properly); and recurrent joint dislocations resulting in joint deformity. Sense of touch, vibration, and position are normal. Anhidrosis predisposes to recurrent febrile episodes that are often the initial manifestation of CIPA. Hypothermia in cold environments also occurs. Intellectual disability of varying degree is observed in most affected individuals; hyperactivity and emotional lability are common.
Last Evaluated: Oct 05, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 1:156879154
OMIM Allelic Variant: 191315.0005
Congenital insensitivity to pain with anhidrosis (CIPA), also known as hereditary sensory and autonomic neuropathy type IV (HSAN IV), is characterized by insensitivity to pain, anhidrosis (the inability to sweat), and intellectual disability. The ability to sense all pain (including visceral pain) is absent, resulting in repeated injuries including: oral self-mutilation (biting of tongue, lips, and buccal mucosa); biting of fingertips; bruising, scarring, and infection of the skin; multiple bone fractures (many of which fail to heal properly); and recurrent joint dislocations resulting in joint deformity. Sense of touch, vibration, and position are normal. Anhidrosis predisposes to recurrent febrile episodes that are often the initial manifestation of CIPA. Hypothermia in cold environments also occurs. Intellectual disability of varying degree is observed in most affected individuals; hyperactivity and emotional lability are common.
Last Evaluated: Oct 05, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 1:156879154
OMIM Allelic Variant: 191315.0005
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Oct 05, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 1:156879154
OMIM Allelic Variant: 191315.0005
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Oct 05, 2017
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 7
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 1:156879154
OMIM Allelic Variant: 191315.0005
Low clinical importance, Uncertain benign — Also called G607V, this variant has been reported as a nonpathogenic polymorphism.
Clinically Significant Conflicting/Uncertain
Hetero
Gene:
ENPP1
Variant:
c.-24G>C
rsID: rs1800948
Ref Allele: G
Alt Allele: C
Freq: 3.665%uncommon
CADD: 3.275
ClinVar Submissions (1)
Generalized arterial calcification of infancy (GACI) is characterized by infantile onset of widespread arterial calcification and/or narrowing of large- and medium-sized vessels resulting in cardiovascular findings (which can include heart failure, respiratory distress, edema, cyanosis, hypertension, and/or cardiomegaly). Additional findings can include extravascular calcifications (particularly periarticular), typical skin and retinal manifestations of pseudoxanthoma elasticum (PXE), hearing loss, and development of rickets after infancy. While mortality in infancy is high, survival into the second and third decade has been reported.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 6:131808012
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 6:131808012
Likely benign
Hetero
Gene:
DYNC1H1
Variant:
c.*232C>T
rsID: rs17512996
Ref Allele: C
Alt Allele: T
Freq: 3.6785%uncommon
CADD: 0.067
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 14:102050795
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 14:102050795
Autosomal dominant cerebellar ataxia (ADCA) describes a clinically and genetically heterogeneous group of neurodegenerative diseases characterized by a slowly progressive ataxia of gait, stance and limbs, dysarthria and/or oculomotor disorder, due to cerebellar degeneration in the absence of coexisting diseases. The degenerative process can be limited to the cerebellum (ADCA type 3) or may additionally involve the retina (ADCA type 2), optic nerve, ponto-medullary systems, basal ganglia, cerebral cortex, spinal tracts or peripheral nerves (ADCA type 1) (see these terms). In ACDA type 4 (see this term), a cerebellar syndrome is associated with epilepsy.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 14:102050795
Likely benign
Hetero
Gene:
MYO5B
Variant:
c.3396+9T>C
rsID: rs75971548
Ref Allele: A
Alt Allele: G
Freq: 3.6825%uncommon
CADD: 9.894
ClinVar Submissions (2)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 18:49877754
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 18:49877754
Benign/Likely benign
Hetero
Gene:
EEF1A2
Variant:
c.207C>T
(p.Arg69=)
rsID: rs3818681
Ref Allele: G
Alt Allele: A
Freq: 3.6976%uncommon
CADD: 1.2
ClinVar Submissions (3)
Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as EPILEPSY or "seizure disorder."
Last Evaluated: Jun 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 20:63495973
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 28, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 20:63495973
Benign
Hetero
Gene:
NFKB2
Variant:
c.2094C>T
(p.Asn698=)
rsID: rs11574851
Ref Allele: C
Alt Allele: T
Freq: 3.704%uncommon
CADD: 4.075
ClinVar Submissions (1)
Common variable immunodeficiency-10 is an autosomal dominant primary immunodeficiency characterized by childhood-onset of recurrent infections, hypogammaglobulinemia, and decreased numbers of memory and marginal zone B cells. Some patients may develop autoimmune features and have circulating autoantibodies. An unusual feature is central adrenal insufficiency (summary by Chen et al., 2013). For a general description and a discussion of genetic heterogeneity of common variable immunodeficiency, see CVID1 (607594).
Last Evaluated: Jul 31, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 10:102401202
Benign
Hetero
Gene:
SMARCA4
Variant:
c.4680C>T
(p.Asp1560=)
rsID: rs9105
Ref Allele: C
Alt Allele: T
Freq: 3.7056%uncommon
CADD: 7.018
ClinVar Submissions (6)
Coffin-Siris syndrome is a multiple malformation syndrome characterized by mental retardation associated with coarse facial features, hypertrichosis, sparse scalp hair, and hypoplastic or absent fifth fingernails or toenails. Other more variable features may include poor overall growth, craniofacial abnormalities, spinal anomalies, and congenital heart defects (review by Vergano and Deardorff, 2014). Mutations in the ARID1B gene are the most common cause of Coffin-Siris syndrome (Wieczorek et al., 2013). Genetic Heterogeneity of Coffin-Siris Syndrome Forms of Coffin-Siris syndrome have been shown to be caused by mutations in genes encoding subunits of the SWI/SNF complex, also known as the BAF complex, which functions as a chromatin remodeling factor. These include CSS2 (614607), caused by mutation in the ARID1A gene (603024); CSS3 (614608), caused by mutation in the SMARCB1 gene (601607); CSS4 (614609), caused by mutation in the SMARCA4 gene (603254); CSS5 (616938), caused by mutation in the SMARCE1 gene (603111); CSS6 (617808), caused by mutation in the ARID2 gene (609539); and CSS7 (618027), caused by mutation in the DPF2 gene (601671). A similar phenotype, Nicolaides-Baraitser syndrome (NCBRS; 601358), is also caused by mutation in a subunit of this complex, i.e., SMARCA2 (600014).
Last Evaluated: Aug 18, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 19:11058838
The condition of a pattern of malignancies within a family, but not every individual's necessarily having the same neoplasm. Characteristically the tumor tends to occur at an earlier than average age, individuals may have more than one primary tumor, the tumors may be multicentric, usually more than 25 percent of the individuals in direct lineal descent from the proband are affected, and the cancer predisposition in these families behaves as an autosomal dominant trait with about 60 percent penetrance.
Last Evaluated: Aug 18, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 19:11058838
Rhabdoid tumor predisposition syndrome (RTPS) is characterized by a markedly increased risk of developing rhabdoid tumors – rare and highly aggressive malignant tumors occurring predominantly in infants and children younger than age three years. Rhabdoid tumors can occur in almost any anatomic location, commonly in the central nervous system (i.e., atypical teratoid/rhabdoid tumor [AT/RT]); more than 50% occur in the cerebellum. Other common locations include extracranial extrarenal malignant rhabdoid tumors (e.g., rhabdoid tumors of the head and neck, paravertebral muscles, liver, bladder, mediastinum, retroperitoneum, pelvis, and heart) (eMRT), rhabdoid tumor of the kidney (RTK), and possibly small-cell carcinoma of the ovary (hypercalcemic type). Individuals with RTPS typically present before age 12 months with synchronous tumors that exhibit aggressive clinical behavior.
Last Evaluated: Aug 18, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 19:11058838
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 18, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 19:11058838
Benign
Hetero
Gene:
MTTP
Variant:
c.1769+14C>T
rsID: rs41275713
Ref Allele: C
Alt Allele: T
Freq: 3.7231%uncommon
CADD: 1.013
ClinVar Submissions (2)
Abetalipoproteinemia typically presents in infancy with failure to thrive, diarrhea, vomiting, and malabsorption of fat. Hematologic manifestations may include acanthocytosis (irregularly spiculated erythrocytes), anemia, reticulocytosis, and hemolysis with resultant hyperbilirubinemia. Malabsorption of fat-soluble vitamins (A, D, E, and K) can result in an increased international normalized ratio (INR). Untreated individuals may develop atypical pigmentation of the retina that may present with progressive loss of night vision and/or color vision in adulthood. Neuromuscular findings in untreated individuals including progressive loss of deep tendon reflexes, vibratory sense, and proprioception; muscle weakness; dysarthria; and ataxia typically manifest in the first or second decades of life.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 4:99608991
Benign/Likely benign
Hetero
Gene:
MTTP
Variant:
c.730C>G
(p.Gln244Glu)
rsID: rs17599091
Ref Allele: C
Alt Allele: G
Freq: 3.7239%uncommon
CADD: 5.607
ClinVar Submissions (3)
Abetalipoproteinemia typically presents in infancy with failure to thrive, diarrhea, vomiting, and malabsorption of fat. Hematologic manifestations may include acanthocytosis (irregularly spiculated erythrocytes), anemia, reticulocytosis, and hemolysis with resultant hyperbilirubinemia. Malabsorption of fat-soluble vitamins (A, D, E, and K) can result in an increased international normalized ratio (INR). Untreated individuals may develop atypical pigmentation of the retina that may present with progressive loss of night vision and/or color vision in adulthood. Neuromuscular findings in untreated individuals including progressive loss of deep tendon reflexes, vibratory sense, and proprioception; muscle weakness; dysarthria; and ataxia typically manifest in the first or second decades of life.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 4:99591762
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 4:99591762
Benign/Likely benign
Hetero
Gene:
SEC23B
Variant:
c.1276G>A
(p.Val426Ile)
rsID: rs41309927
Ref Allele: G
Alt Allele: A
Freq: 3.7287%uncommon
CADD: 18.86
ClinVar Submissions (3)
Congenital dyserythropoietic anemia (CDA) is an inherited blood disorder that affects the development of red blood cells. This disorder is one of many types of anemia, which is a condition characterized by a shortage of red blood cells. This shortage prevents the blood from carrying an adequate supply of oxygen to the body's tissues. The resulting symptoms can include tiredness (fatigue), weakness, pale skin, and other complications.Researchers have identified three major types of CDA: type I, type II, and type III. The types have different genetic causes and different but overlapping patterns of signs and symptoms.CDA type I is characterized by moderate to severe anemia. It is usually diagnosed in childhood or adolescence, although in some cases, the condition can be detected before birth. Many affected individuals have yellowing of the skin and eyes (jaundice) and an enlarged liver and spleen (hepatosplenomegaly). This condition also causes the body to absorb too much iron, which builds up and can damage tissues and organs. In particular, iron overload can lead to an abnormal heart rhythm (arrhythmia), congestive heart failure, diabetes, and chronic liver disease (cirrhosis). Rarely, people with CDA type I are born with skeletal abnormalities, most often involving the fingers and/or toes.The anemia associated with CDA type II can range from mild to severe, and most affected individuals have jaundice, hepatosplenomegaly, and the formation of hard deposits in the gallbladder called gallstones. This form of the disorder is usually diagnosed in adolescence or early adulthood. An abnormal buildup of iron typically occurs after age 20, leading to complications including heart disease, diabetes, and cirrhosis.The signs and symptoms of CDA type III tend to be milder than those of the other types. Most affected individuals do not have hepatosplenomegaly, and iron does not build up in tissues and organs. In adulthood, abnormalities of a specialized tissue at the back of the eye (the retina) can cause vision impairment. Some people with CDA type III also have a blood disorder known as monoclonal gammopathy, which can lead to a cancer of white blood cells (multiple myeloma).Several other variants of CDA have been described, although they appear to be rare and not much is known about them. Once researchers discover the genetic causes of these variants, some of them may be grouped with the three major types of CDA.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 20:18532706
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 20:18532706
Benign/Likely benign
Hetero
Gene:
CTNS
Variant:
c.*1633C>G
rsID: rs112032534
Ref Allele: C
Alt Allele: G
Freq: 3.7446%uncommon
CADD: 1.354
ClinVar Submissions (1)
Cystinosis comprises three allelic phenotypes: Nephropathic cystinosis in untreated children is characterized by renal Fanconi syndrome, poor growth, hypophosphatemic/calcipenic rickets, impaired glomerular function resulting in complete glomerular failure, and accumulation of cystine in almost all cells, leading to cellular dysfunction with tissue and organ impairment. The typical untreated child has short stature, rickets, and photophobia. Failure to thrive is generally noticed after approximately age six months; signs of renal tubular Fanconi syndrome (polyuria, polydipsia, dehydration, and acidosis) appear as early as age six months; corneal crystals can be present before age one year and are always present after age 16 months. Prior to the use of renal transplantation and cystine-depleting therapy, the life span in nephropathic cystinosis was no longer than ten years. With these interventions, affected individuals can survive at least into the mid-forties or fifties with satisfactory quality of life. Intermediate cystinosis is characterized by all the typical manifestations of nephropathic cystinosis, but onset is at a later age. Renal glomerular failure occurs in all untreated affected individuals, usually between ages 15 and 25 years. The non-nephropathic (ocular) form of cystinosis is characterized clinically only by photophobia resulting from corneal cystine crystal accumulation.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 17:3662002
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 17:3662002
Likely benign
Hetero
Gene:
OGDH
Variant:
c.345A>G
(p.Glu115=)
rsID: rs11557280
Ref Allele: A
Alt Allele: G
Freq: 3.7462%uncommon
CADD: 2.996
ClinVar Submissions (1)
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Feb 22, 2016
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 7:44645449
Benign
Homo
Gene:
CTNS
Variant:
c.*1595C>T
rsID: rs112299490
Ref Allele: C
Alt Allele: T
Freq: 3.7462%uncommon
CADD: 0.762
ClinVar Submissions (1)
Cystinosis comprises three allelic phenotypes: Nephropathic cystinosis in untreated children is characterized by renal Fanconi syndrome, poor growth, hypophosphatemic/calcipenic rickets, impaired glomerular function resulting in complete glomerular failure, and accumulation of cystine in almost all cells, leading to cellular dysfunction with tissue and organ impairment. The typical untreated child has short stature, rickets, and photophobia. Failure to thrive is generally noticed after approximately age six months; signs of renal tubular Fanconi syndrome (polyuria, polydipsia, dehydration, and acidosis) appear as early as age six months; corneal crystals can be present before age one year and are always present after age 16 months. Prior to the use of renal transplantation and cystine-depleting therapy, the life span in nephropathic cystinosis was no longer than ten years. With these interventions, affected individuals can survive at least into the mid-forties or fifties with satisfactory quality of life. Intermediate cystinosis is characterized by all the typical manifestations of nephropathic cystinosis, but onset is at a later age. Renal glomerular failure occurs in all untreated affected individuals, usually between ages 15 and 25 years. The non-nephropathic (ocular) form of cystinosis is characterized clinically only by photophobia resulting from corneal cystine crystal accumulation.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 17:3661964
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 17:3661964
Likely benign
Hetero
Gene:
CTNS
Variant:
c.*1866C>T
rsID: rs111430685
Ref Allele: C
Alt Allele: T
Freq: 3.7637%uncommon
CADD: 0.862
ClinVar Submissions (1)
Cystinosis comprises three allelic phenotypes: Nephropathic cystinosis in untreated children is characterized by renal Fanconi syndrome, poor growth, hypophosphatemic/calcipenic rickets, impaired glomerular function resulting in complete glomerular failure, and accumulation of cystine in almost all cells, leading to cellular dysfunction with tissue and organ impairment. The typical untreated child has short stature, rickets, and photophobia. Failure to thrive is generally noticed after approximately age six months; signs of renal tubular Fanconi syndrome (polyuria, polydipsia, dehydration, and acidosis) appear as early as age six months; corneal crystals can be present before age one year and are always present after age 16 months. Prior to the use of renal transplantation and cystine-depleting therapy, the life span in nephropathic cystinosis was no longer than ten years. With these interventions, affected individuals can survive at least into the mid-forties or fifties with satisfactory quality of life. Intermediate cystinosis is characterized by all the typical manifestations of nephropathic cystinosis, but onset is at a later age. Renal glomerular failure occurs in all untreated affected individuals, usually between ages 15 and 25 years. The non-nephropathic (ocular) form of cystinosis is characterized clinically only by photophobia resulting from corneal cystine crystal accumulation.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 17:3662235
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 17:3662235
Likely benign
Hetero
Gene:
GRIK2
Variant:
c.1281C>G
(p.Ser427=)
rsID: rs34747916
Ref Allele: C
Alt Allele: G
Freq: 3.8266%uncommon
CADD: 4.353
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 6:101818447
Likely benign
Hetero
Gene:
TNPO3
Variant:
c.2358G>A
(p.Leu786=)
rsID: rs11538884
Ref Allele: C
Alt Allele: T
Freq: 3.8354%uncommon
CADD: 9.664
ClinVar Submissions (2)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Feb 26, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 7:128972498
Benign
Hetero
Gene:
MRE11
Variant:
c.*511G>A
rsID: rs13447749
Ref Allele: C
Alt Allele: T
Freq: 3.8362%uncommon
CADD: 2.356
ClinVar Submissions (1)
Ataxia-telangiectasia-like disorder-1 is an autosomal recessive disorder characterized clinically by progressive cerebellar degeneration resulting in ataxia and oculomotor apraxia. Laboratory studies of patient cells showed increased susceptibility to radiation, consistent with a defect in DNA repair. The disorder shares some phenotypic features of ataxia-telangiectasia (AT; 208900), but telangiectases and immune deficiency are not present in ATLD1 (summary by Hernandez et al., 1993 and Stewart et al., 1999). Genetic Heterogeneity of Ataxia-Telangiectasia-Like Disorder See also ATLD2 (615919), caused by mutation in the PCNA gene (176740) on chromosome 20p12.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 11:94419614
Likely benign
Hetero
Gene:
BMP1;SFTPC
Variant:
c.201+14G>A
rsID: rs8192327
Ref Allele: G
Alt Allele: A
Freq: 3.8394%uncommon
CADD: 5.996
ClinVar Submissions (2)
Familial pulmonary fibrosis (FPF in this GeneReview) is defined as idiopathic interstitial pneumonia (IIP) in two or more first-degree relatives (parent, sib, or offspring). Up to 20% of cases of IIP cluster in families. The clinical findings of IIP are bibasilar reticular abnormalities, ground glass opacities, or diffuse nodular lesions on high-resolution computed tomography and abnormal pulmonary function studies that include evidence of restriction (reduced VC with an increase in FEV1/FVC ratio) and/or impaired gas exchange (increased P(A-a)O2 with rest or exercise or decreased diffusion capacity of the lung for carbon monoxide [DLCO]). FPF usually presents between ages 50 and 70 years. FPF may be complicated by lung cancer; bronchoalveolar cell carcinoma, small-cell carcinoma, and adenocarcinoma have been described.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 8:22162746
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 8:22162746
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 8:22162746
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 8:22162746
Benign/Likely benign
Hetero
Gene:
HAND1
Variant:
c.531G>C
(p.Arg177=)
rsID: rs34198899
Ref Allele: C
Alt Allele: G
Freq: 3.8696%uncommon
CADD: 15.15
ClinVar Submissions (1)
Critical congenital heart disease (CCHD) is a term that refers to a group of serious heart defects that are present from birth. These abnormalities result from problems with the formation of one or more parts of the heart during the early stages of embryonic development. CCHD prevents the heart from pumping blood effectively or reduces the amount of oxygen in the blood. As a result, organs and tissues throughout the body do not receive enough oxygen, which can lead to organ damage and life-threatening complications. Individuals with CCHD usually require surgery soon after birth.Although babies with CCHD may appear healthy for the first few hours or days of life, signs and symptoms soon become apparent. These can include an abnormal heart sound during a heartbeat (heart murmur), rapid breathing (tachypnea), low blood pressure (hypotension), low levels of oxygen in the blood (hypoxemia), and a blue or purple tint to the skin caused by a shortage of oxygen (cyanosis). If untreated, CCHD can lead to shock, coma, and death. However, most people with CCHD now survive past infancy due to improvements in early detection, diagnosis, and treatment.Some people with treated CCHD have few related health problems later in life. However, long-term effects of CCHD can include delayed development and reduced stamina during exercise. Adults with these heart defects have an increased risk of abnormal heart rhythms, heart failure, sudden cardiac arrest, stroke, and premature death.Each of the heart defects associated with CCHD affects the flow of blood into, out of, or through the heart. Some of the heart defects involve structures within the heart itself, such as the two lower chambers of the heart (the ventricles) or the valves that control blood flow through the heart. Others affect the structure of the large blood vessels leading into and out of the heart (including the aorta and pulmonary artery). Still others involve a combination of these structural abnormalities.People with CCHD have one or more specific heart defects. The heart defects classified as CCHD include coarctation of the aorta, double-outlet right ventricle, D-transposition of the great arteries, Ebstein anomaly, hypoplastic left heart syndrome, interrupted aortic arch, pulmonary atresia with intact septum, single ventricle, total anomalous pulmonary venous connection, tetralogy of Fallot, tricuspid atresia, and truncus arteriosus.
Last Evaluated: Aug 04, 2017
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 5:154477478
Benign
Hetero
Gene:
PDE6G
Variant:
c.*393C>T
rsID: rs57654048
Ref Allele: G
Alt Allele: A
Freq: 3.8832%uncommon
CADD: 2.29
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 17:81650681
Likely benign
Hetero
Gene:
ITGB2
Variant:
c.499+7C>T
rsID: rs17004715
Ref Allele: G
Alt Allele: A
Freq: 3.8848%uncommon
CADD: 5.774
ClinVar Submissions (2)
A rare autosomal recessive immunodeficiency disorder caused by deficiency of CD18 expression. It is characterized by defects in neutrophil adhesion and bacterial infections.
Last Evaluated: Aug 10, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 21:44903358
Leukocyte adhesion deficiency (LAD) is an autosomal recessive disorder of neutrophil function resulting from a deficiency of the beta-2 integrin subunit of the leukocyte cell adhesion molecule. The leukocyte cell adhesion molecule is present on the surface of peripheral blood mononuclear leukocytes and granulocytes and mediates cell-cell and cell-extracellular matrix adhesion. LAD is characterized by recurrent bacterial infections; impaired pus formation and wound healing; abnormalities of a wide variety of adhesion-dependent functions of granulocytes, monocytes, and lymphocytes; and a lack of beta-2/alpha-L, beta-2/alpha-M, and beta-2/alpha-X expression.
Last Evaluated: Aug 10, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 21:44903358
Benign/Likely benign
Homo
Gene:
GJB2
Variant:
c.*931C>T
rsID: rs5030700
Ref Allele: G
Alt Allele: A
Freq: 3.8927%uncommon
CADD: 5.265
ClinVar Submissions (1)
Hystrix-like ichthyosis with deafness (HID) is a disorder characterized by dry, scaly skin (ichthyosis) and hearing loss that is usually profound. Hystrix-like means resembling a porcupine; in this type of ichthyosis, the scales may be thick and spiky, giving the appearance of porcupine quills.Newborns with HID typically develop reddened skin. The skin abnormalities worsen over time, and the ichthyosis eventually covers most of the body, although the palms of the hands and soles of the feet are usually only mildly affected. Breaks in the skin may occur and in severe cases can lead to life-threatening infections. Affected individuals have an increased risk of developing a type of skin cancer called squamous cell carcinoma, which can also affect mucous membranes such as the inner lining of the mouth. People with HID may also have patchy hair loss caused by scarring on particular areas of skin.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 13:20187970
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 13:20187970
Vohwinkel syndrome is a disorder with classic and variant forms, both of which affect the skin.In the classic form of Vohwinkel syndrome, affected individuals have thick, honeycomb-like calluses on the palms of the hands and soles of the feet (palmoplantar keratoses) beginning in infancy or early childhood. Affected children also typically have distinctive starfish-shaped patches of thickened skin on the tops of the fingers and toes or on the knees. Within a few years they develop tight bands of abnormal fibrous tissue around their fingers and toes (pseudoainhum); the bands may cut off the circulation to the digits and result in spontaneous amputation. People with the classic form of the disorder also have hearing loss.The variant form of Vohwinkel syndrome does not involve hearing loss, and the skin features also include widespread dry, scaly skin (ichthyosis), especially on the limbs. The ichthyosis is usually mild, and there may also be mild reddening of the skin (erythroderma). Some affected infants are born with a tight, clear sheath covering their skin called a collodion membrane. This membrane is usually shed during the first few weeks of life.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 13:20187970
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 13:20187970
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 13:20187970
Benign
Hetero
Gene:
GJB2
Variant:
c.*168A>G
rsID: rs55704559
Ref Allele: T
Alt Allele: C
Freq: 3.9094%uncommon
CADD: 1.066
ClinVar Submissions (1)
Hystrix-like ichthyosis with deafness (HID) is a disorder characterized by dry, scaly skin (ichthyosis) and hearing loss that is usually profound. Hystrix-like means resembling a porcupine; in this type of ichthyosis, the scales may be thick and spiky, giving the appearance of porcupine quills.Newborns with HID typically develop reddened skin. The skin abnormalities worsen over time, and the ichthyosis eventually covers most of the body, although the palms of the hands and soles of the feet are usually only mildly affected. Breaks in the skin may occur and in severe cases can lead to life-threatening infections. Affected individuals have an increased risk of developing a type of skin cancer called squamous cell carcinoma, which can also affect mucous membranes such as the inner lining of the mouth. People with HID may also have patchy hair loss caused by scarring on particular areas of skin.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 13:20188733
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 13:20188733
Vohwinkel syndrome is a disorder with classic and variant forms, both of which affect the skin.In the classic form of Vohwinkel syndrome, affected individuals have thick, honeycomb-like calluses on the palms of the hands and soles of the feet (palmoplantar keratoses) beginning in infancy or early childhood. Affected children also typically have distinctive starfish-shaped patches of thickened skin on the tops of the fingers and toes or on the knees. Within a few years they develop tight bands of abnormal fibrous tissue around their fingers and toes (pseudoainhum); the bands may cut off the circulation to the digits and result in spontaneous amputation. People with the classic form of the disorder also have hearing loss.The variant form of Vohwinkel syndrome does not involve hearing loss, and the skin features also include widespread dry, scaly skin (ichthyosis), especially on the limbs. The ichthyosis is usually mild, and there may also be mild reddening of the skin (erythroderma). Some affected infants are born with a tight, clear sheath covering their skin called a collodion membrane. This membrane is usually shed during the first few weeks of life.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 13:20188733
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 13:20188733
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 13:20188733
Benign
Hetero
Gene:
MOGS
Variant:
c.184G>A
(p.Val62Met)
rsID: rs79181168
Ref Allele: C
Alt Allele: T
Freq: 3.9309%uncommon
CADD: 16.59
ClinVar Submissions (3)
A genetically heterogeneous group of heritable disorders resulting from defects in protein N-glycosylation.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:74465064
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:74465064
Benign/Likely benign
Hetero
Gene:
CACNA1C
Variant:
c.4038C>T
(p.Ile1346=)
rsID: rs56180838
Ref Allele: C
Alt Allele: T
Freq: 3.9708%uncommon
CADD: 12.57
ClinVar Submissions (5)
Brugada syndrome is characterized by cardiac conduction abnormalities (ST-segment abnormalities in leads V1-V3 on ECG and a high risk for ventricular arrhythmias) that can result in sudden death. Brugada syndrome presents primarily during adulthood although age at diagnosis may range from infancy to late adulthood. The mean age of sudden death is approximately 40 years. Clinical presentations may also include sudden infant death syndrome (SIDS; death of a child during the first year of life without an identifiable cause) and the sudden unexpected nocturnal death syndrome (SUNDS), a typical presentation in individuals from Southeast Asia. Other conduction defects can include first-degree AV block, intraventricular conduction delay, right bundle branch block, and sick sinus syndrome.
Last Evaluated: Aug 08, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:2651732
Last Evaluated: Aug 08, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:2651732
Last Evaluated: Aug 08, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:2651732
A condition that is characterized by episodes of fainting (SYNCOPE) and varying degree of ventricular arrhythmia as indicated by the prolonged QT interval. The inherited forms are caused by mutation of genes encoding cardiac ion channel proteins. The two major forms are ROMANO-WARD SYNDROME and JERVELL-LANGE NIELSEN SYNDROME.
Last Evaluated: Aug 08, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:2651732
Timothy syndrome is a multisystem disorder characterized by cardiac, hand/foot, facial, and neurodevelopmental features. Typical cardiac findings include a rate-corrected QT interval >480 ms, functional 2:1 AV block with bradycardia, tachyarrhythmias, and congenital heart defects (patent ductus arteriosus, patent foramen ovale, ventricular septal defect, tetralogy of Fallot, hypertrophic cardiomyopathy). The diagnosis of Timothy syndrome is generally made within the first few days of life although it may be suspected prenatally due to 2:1 AV block or bradycardia in the fetus. Hand/foot findings are unilateral or bilateral cutaneous syndactyly variably involving fingers two (index), three (middle), four (ring), and five (little) and bilateral cutaneous syndactyly of toes two and three. Facial findings include depressed nasal bridge, low-set ears, thin vermilion border of the upper lip, and round face. Neuropsychiatric involvement includes global developmental delays and autism spectrum disorders. Ventricular tachyarrhythmia is the leading cause of death, followed by infection and complications of intractable hypoglycemia. Average age of death is 2.5 years.
Last Evaluated: Aug 08, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:2651732
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 08, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:2651732
Benign/Likely benign
Homo
Gene:
RYR2
Variant:
c.*129C>G
rsID: rs16835891
Ref Allele: C
Alt Allele: G
Freq: 4.0042%uncommon
CADD: 0.131
ClinVar Submissions (1)
Arrhythmogenic right ventricular cardiomyopathy (ARVC) – previously referred to as arrhythmogenic right ventricular dysplasia (ARVD) – is characterized by progressive fibrofatty replacement of the myocardium that predisposes to ventricular tachycardia and sudden death in young individuals and athletes. It primarily affects the right ventricle, and it may also involve the left ventricle. The presentation of disease is highly variable even within families, and some affected individuals may not meet established clinical criteria. The mean age at diagnosis is 31 years (±13; range: 4-64 years).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:237832776
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is characterized by episodic syncope occurring during exercise or acute emotion in individuals without structural cardiac abnormalities. The underlying cause of these episodes is the onset of fast ventricular tachycardia (bidirectional or polymorphic). Spontaneous recovery may occur when these arrhythmias self-terminate. In other instances, ventricular tachycardia may degenerate into ventricular fibrillation and cause sudden death if cardiopulmonary resuscitation is not readily available. The mean age of onset of symptoms (usually a syncopal episode) is between age seven and twelve years; onset as late as the fourth decade of life has been reported. If untreated, CPVT is highly lethal, as approximately 30% of affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. Sudden death may be the first manifestation of the disease.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:237832776
Likely benign
Hetero
Gene:
COL9A3
Variant:
c.1548+16G>A
rsID: rs3765462
Ref Allele: G
Alt Allele: A
Freq: 4.0066%uncommon
CADD: 0.024
ClinVar Submissions (2)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jan 04, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 20:62836349
Benign
Hetero
Gene:
EVC
Variant:
c.769C>T
(p.Leu257=)
rsID: rs6446393
Ref Allele: C
Alt Allele: T
Freq: 4.0098%uncommon
CADD: 5.776
ClinVar Submissions (4)
Weyers acrofacial dysostosis is an autosomal dominant condition with dental anomalies, nail dystrophy, postaxial polydactyly, and mild short stature. Ellis-van Creveld syndrome is a similar disorder, with autosomal recessive inheritance and the additional features of disproportionate dwarfism, thoracic dysplasia, and congenital heart disease (summary by Howard et al., 1997).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 4:5741782
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 4:5741782
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 4:5741782
Benign
Hetero
Gene:
TRIOBP
Variant:
c.5487+9A>G
rsID: rs56016429
Ref Allele: A
Alt Allele: G
Freq: 4.0146%uncommon
CADD: 0.835
ClinVar Submissions (4)
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jul 31, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 22:37754993
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 31, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 22:37754993
Benign
Hetero
Gene:
MOCS1
Variant:
c.*212G>T
rsID: rs11969206
Ref Allele: C
Alt Allele: A
Freq: 4.0249%uncommon
CADD: 0.98
ClinVar Submissions (1)
Molybdenum cofactor deficiency (MOCOD) is a rare autosomal recessive metabolic disorder characterized by onset in infancy of poor feeding, intractable seizures, and severe psychomotor retardation. Characteristic biochemical abnormalities include decreased serum uric acid and increased urine sulfite levels due to the combined enzymatic deficiency of xanthine dehydrogenase (XDH; 607633) and sulfite oxidase (SUOX; 606887), both of which use molybdenum as a cofactor. Most affected individuals die in early childhood (summary by Reiss, 2000; Reiss et al., 2011). Genetic Heterogeneity of Molybdenum Cofactor Deficiency See also MOCOD, complementation group B (MOCODB; 252160), caused by mutation in the MOCS2 gene (602708) on chromosome 5q11; and MOCOD, complementation group C (MOCODC; 615501), caused by mutation in the GPHN gene (603930) on chromosome 14q24.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 6:39906913
Likely benign
Hetero
Gene:
MOCS1
Variant:
c.*26C>A
rsID: rs11969769
Ref Allele: G
Alt Allele: T
Freq: 4.0249%uncommon
CADD: 0.216
ClinVar Submissions (1)
Molybdenum cofactor deficiency (MOCOD) is a rare autosomal recessive metabolic disorder characterized by onset in infancy of poor feeding, intractable seizures, and severe psychomotor retardation. Characteristic biochemical abnormalities include decreased serum uric acid and increased urine sulfite levels due to the combined enzymatic deficiency of xanthine dehydrogenase (XDH; 607633) and sulfite oxidase (SUOX; 606887), both of which use molybdenum as a cofactor. Most affected individuals die in early childhood (summary by Reiss, 2000; Reiss et al., 2011). Genetic Heterogeneity of Molybdenum Cofactor Deficiency See also MOCOD, complementation group B (MOCODB; 252160), caused by mutation in the MOCS2 gene (602708) on chromosome 5q11; and MOCOD, complementation group C (MOCODC; 615501), caused by mutation in the GPHN gene (603930) on chromosome 14q24.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 6:39907099
Likely benign
Hetero
Gene:
MOCS1
Variant:
c.*69G>C
rsID: rs11969233
Ref Allele: C
Alt Allele: G
Freq: 4.0257%uncommon
CADD: 4.365
ClinVar Submissions (1)
Molybdenum cofactor deficiency (MOCOD) is a rare autosomal recessive metabolic disorder characterized by onset in infancy of poor feeding, intractable seizures, and severe psychomotor retardation. Characteristic biochemical abnormalities include decreased serum uric acid and increased urine sulfite levels due to the combined enzymatic deficiency of xanthine dehydrogenase (XDH; 607633) and sulfite oxidase (SUOX; 606887), both of which use molybdenum as a cofactor. Most affected individuals die in early childhood (summary by Reiss, 2000; Reiss et al., 2011). Genetic Heterogeneity of Molybdenum Cofactor Deficiency See also MOCOD, complementation group B (MOCODB; 252160), caused by mutation in the MOCS2 gene (602708) on chromosome 5q11; and MOCOD, complementation group C (MOCODC; 615501), caused by mutation in the GPHN gene (603930) on chromosome 14q24.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 6:39907056
Likely benign
Hetero
Gene:
CACNB2
Variant:
c.-200232C>A
rsID: rs138094231
Ref Allele: C
Alt Allele: A
Freq: 4.0353%uncommon
CADD: 13.76
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 25, 2013
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 10:18140695
Benign
Hetero
Gene:
LHX4
Variant:
c.450C>T
(p.Asn150=)
rsID: rs16855642
Ref Allele: C
Alt Allele: T
Freq: 4.0496%uncommon
CADD: 15.67
ClinVar Submissions (3)
Last Evaluated: Apr 21, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:180266593
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Apr 21, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:180266593
Benign/Likely benign
Hetero
Gene:
MOCS1
Variant:
c.*657C>T
rsID: rs41273138
Ref Allele: G
Alt Allele: A
Freq: 4.0791%uncommon
CADD: 0.485
ClinVar Submissions (1)
Molybdenum cofactor deficiency (MOCOD) is a rare autosomal recessive metabolic disorder characterized by onset in infancy of poor feeding, intractable seizures, and severe psychomotor retardation. Characteristic biochemical abnormalities include decreased serum uric acid and increased urine sulfite levels due to the combined enzymatic deficiency of xanthine dehydrogenase (XDH; 607633) and sulfite oxidase (SUOX; 606887), both of which use molybdenum as a cofactor. Most affected individuals die in early childhood (summary by Reiss, 2000; Reiss et al., 2011). Genetic Heterogeneity of Molybdenum Cofactor Deficiency See also MOCOD, complementation group B (MOCODB; 252160), caused by mutation in the MOCS2 gene (602708) on chromosome 5q11; and MOCOD, complementation group C (MOCODC; 615501), caused by mutation in the GPHN gene (603930) on chromosome 14q24.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 6:39906468
Likely benign
Hetero
Gene:
COL9A3
Variant:
c.307C>T
(p.Arg103Trp)
rsID: rs61734651
Ref Allele: C
Alt Allele: T
Freq: 4.0791%uncommon
CADD: 26.3
ClinVar Submissions (5)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign, risk factor
Assembly: GRCh38
Chromosome/Position: 20:62819980
OMIM Allelic Variant: 120270.0003
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign, risk factor
Assembly: GRCh38
Chromosome/Position: 20:62819980
OMIM Allelic Variant: 120270.0003
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign, risk factor
Assembly: GRCh38
Chromosome/Position: 20:62819980
OMIM Allelic Variant: 120270.0003
Moderate clinical importance, Likely pathogenic — Carriers of this collagen variant are associated with having a significantly increased risk of lumbar disc disease (~11% total risk compared to a typical risk of 4%).
Benign/Likely benign, risk factor
Hetero
Gene:
AKR1D1
Variant:
c.*1311A>C
rsID: rs188138947
Ref Allele: A
Alt Allele: C
Freq: 4.0862%uncommon
CADD: 4.47
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 7:138117973
Likely benign
Hetero
Gene:
GRIN2A
Variant:
c.*7324G>A
rsID: rs16966244
Ref Allele: C
Alt Allele: T
Freq: 4.0894%uncommon
CADD: 1.836
ClinVar Submissions (1)
GRIN2A-related speech disorders and epilepsy are characterized by speech disorders in all affected individuals and a range of epilepsy syndromes present in about 90%. Severe speech disorders observed can include dysarthria and speech dyspraxia, and both receptive and expressive language delay/regression; more mildly affected individuals may display subtly impaired intelligibility of conversational speech. Epilepsy features include seizure onset usually between ages three and six years, focal epilepsy with language and/or global developmental regression, and electroencephalogram (EEG) showing continuous spike-and-wave discharges in sleep or very active centrotemporal discharges. Seizure types include seizures associated with aura of perioral paresthesia, focal or focal motor seizures (often evolving to generalized tonic-clonic), and atypical absence seizures. Epilepsy syndromes can include: Landau-Kleffner syndrome (LKS), epileptic encephalopathy with continuous spike-and-wave during sleep (ECSWS), childhood epilepsy with centrotemporal spikes (CECTS), atypical childhood epilepsy with centrotemporal spikes (ACECTS), autosomal dominant rolandic epilepsy with speech dyspraxia (ADRESD), and infantile-onset epileptic encephalopathy.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 16:9755825
Benign
Hetero
Gene:
DSP
Variant:
c.8175C>A
(p.Arg2725=)
rsID: rs11558731
Ref Allele: C
Alt Allele: A
Freq: 4.1229%uncommon
CADD: 14.28
ClinVar Submissions (5)
Arrhythmogenic right ventricular cardiomyopathy (ARVC) – previously referred to as arrhythmogenic right ventricular dysplasia (ARVD) – is characterized by progressive fibrofatty replacement of the myocardium that predisposes to ventricular tachycardia and sudden death in young individuals and athletes. It primarily affects the right ventricle, and it may also involve the left ventricle. The presentation of disease is highly variable even within families, and some affected individuals may not meet established clinical criteria. The mean age at diagnosis is 31 years (±13; range: 4-64 years).
Last Evaluated: Aug 17, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:7585437
Arrhythmogenic right ventricular cardiomyopathy (ARVC) – previously referred to as arrhythmogenic right ventricular dysplasia (ARVD) – is characterized by progressive fibrofatty replacement of the myocardium that predisposes to ventricular tachycardia and sudden death in young individuals and athletes. It primarily affects the right ventricle, and it may also involve the left ventricle. The presentation of disease is highly variable even within families, and some affected individuals may not meet established clinical criteria. The mean age at diagnosis is 31 years (±13; range: 4-64 years).
Last Evaluated: Aug 17, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:7585437
Last Evaluated: Aug 17, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:7585437
This syndrome has characteristics of woolly hair, palmoplantar keratoderma and dilated cardiomyopathy principally affecting the left ventricle. Only a few cases have been reported, all involving patients from Ecuador, India or Turkey. The woolly hair is present at birth and the palmoplantar keratoderma appears during the first year of life. The cardiac anomaly presents during childhood and is marked by dilation of the left ventricle accompanied by alterations in muscle contractility. The syndrome is transmitted as an autosomal recessive trait and is caused by mutations in the DSP gene (6p24) encoding desmoplakin, a protein involved in cell adhesion. The syndrome is similar to Naxos disease.
Last Evaluated: Aug 17, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:7585437
A suprabasal subtype of epidermolysis bullosa simplex characterised by generalised superficial erosions and less commonly blistering. Prevalence is unknown but 11 cases have been reported to date. Onset of the disease is usually at birth with skin blistering and generalised erythema which rapidly regresses. The disease is due to mutations in the PKP1 (1q32) gene encoding plakophilin-1. Transmission is autosomal recessive.
Last Evaluated: Aug 17, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:7585437
Last Evaluated: Aug 17, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:7585437
Last Evaluated: Aug 17, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:7585437
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 17, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:7585437
Benign/Likely benign
Hetero
Gene:
DRC1
Variant:
c.2200G>A
(p.Val734Met)
rsID: rs35313480
Ref Allele: G
Alt Allele: A
Freq: 4.1428%uncommon
CADD: 16.23
ClinVar Submissions (2)
Primary ciliary dyskinesia (PCD) is associated with situs abnormalities, abnormal sperm motility, and abnormal ciliary structure and function that result in retention of mucus and bacteria in the respiratory tract leading to chronic otosinopulmonary disease. More than 75% of full-term neonates with PCD have "neonatal respiratory distress" requiring supplemental oxygen for days to weeks. Chronic airway infection, apparent in early childhood, results in bronchiectasis that is almost uniformly present in adulthood. Nasal congestion and sinus infections, apparent in early childhood, persist through adulthood. Chronic/recurrent ear infection, apparent in most young children, can be associated with transient or later irreversible hearing loss. Situs inversus totalis (mirror-image reversal of all visceral organs with no apparent physiologic consequences) is present in 40%-50% of individuals with PCD; heterotaxy (discordance of right and left patterns of ordinarily asymmetric structures that can be associated with significant malformations) is present in approximately 12%. Virtually all males with PCD are infertile as a result of abnormal sperm motility.
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:26456494
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:26456494
Benign
Hetero
Gene:
ATP5MC3
Variant:
c.348T>C
(p.Tyr116=)
rsID: rs8106
Ref Allele: A
Alt Allele: G
Freq: 4.1428%uncommon
CADD: 21
ClinVar Submissions (1)
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Feb 23, 2016
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:175178369
Benign
Hetero
Gene:
ARHGAP31
Variant:
c.*1156C>G
rsID: rs115630304
Ref Allele: C
Alt Allele: G
Freq: 4.1635%uncommon
CADD: 0.395
ClinVar Submissions (1)
Adams-Oliver syndrome (AOS) is characterized by aplasia cutis congenita (ACC) of the scalp and terminal transverse limb defects (TTLD). ACC lesions usually occur in the midline of the parietal or occipital regions, but can also occur on the abdomen or limbs. At birth, an ACC lesion may already have the appearance of a healed scar. ACC lesions less than 5 cm often involve only the skin and almost always heal over a period of months; larger lesions are more likely to involve the skull and possibly the dura, and are at greater risk for complications, which can include infection, hemorrhage, or thrombosis, and can result in death. The limb defects range from mild (unilateral or bilateral short distal phalanges) to severe (complete absence of all toes or fingers, feet or hands, or more, often resembling an amputation). The lower extremities are almost always more severely affected than the upper extremities. Additional major features frequently include cardiovascular malformations/dysfunction (23%), brain anomalies, and less frequently renal, liver, and eye anomalies.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 3:119417420
Likely benign
Hetero
Gene:
ARHGAP31
Variant:
c.*1176T>G
rsID: rs114261128
Ref Allele: T
Alt Allele: G
Freq: 4.1635%uncommon
CADD: 1.23
ClinVar Submissions (1)
Adams-Oliver syndrome (AOS) is characterized by aplasia cutis congenita (ACC) of the scalp and terminal transverse limb defects (TTLD). ACC lesions usually occur in the midline of the parietal or occipital regions, but can also occur on the abdomen or limbs. At birth, an ACC lesion may already have the appearance of a healed scar. ACC lesions less than 5 cm often involve only the skin and almost always heal over a period of months; larger lesions are more likely to involve the skull and possibly the dura, and are at greater risk for complications, which can include infection, hemorrhage, or thrombosis, and can result in death. The limb defects range from mild (unilateral or bilateral short distal phalanges) to severe (complete absence of all toes or fingers, feet or hands, or more, often resembling an amputation). The lower extremities are almost always more severely affected than the upper extremities. Additional major features frequently include cardiovascular malformations/dysfunction (23%), brain anomalies, and less frequently renal, liver, and eye anomalies.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 3:119417440
Likely benign
Hetero
Gene:
CASP10
Variant:
c.1228G>A
(p.Val410Ile)
rsID: rs13010627
Ref Allele: G
Alt Allele: A
Freq: 4.1906%uncommon
CADD: 15.67
ClinVar Submissions (2)
Autoimmune lymphoproliferative syndrome (ALPS), caused by defective lymphocyte homeostasis, is characterized by the following: Non-malignant lymphoproliferation (lymphadenopathy, hepatosplenomegaly with or without hypersplenism) that often improves with age. Autoimmune disease, mostly directed toward blood cells. Lifelong increased risk for both Hodgkin and non-Hodgkin lymphoma. In ALPS-FAS (the most common and best-characterized type of ALPS, associated with heterozygous germline pathogenic variants in FAS), non-malignant lymphoproliferation typically manifests in the first years of life, inexplicably waxes and wanes, and then often decreases without treatment in the second decade of life; in many affected individuals, however, neither splenomegaly nor the overall expansion of lymphocyte subsets in peripheral blood decreases. Although autoimmunity is often not present at the time of diagnosis or at the time of the most extensive lymphoproliferation, autoantibodies can be detected before autoimmune disease manifests clinically. In ALPS-FAS caused by homozygous or compound heterozygous (biallelic) pathogenic variants in FAS, severe lymphoproliferation occurs before, at, or shortly after birth, and usually results in death at an early age. ALPS-sFAS, resulting from somatic FAS pathogenic variants in selected cell populations, notably the alpha/beta double-negative T cells (a/ß-DNT cells), appears to be similar to ALPS-FAS resulting from heterozygous germline pathogenic variants in FAS, although lower incidence of splenectomy and lower lymphocyte counts have been reported in ALPS-sFAS and no cases of lymphoma have yet been published.
Last Evaluated: Aug 02, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:201209375
A rare, primary immunodeficiency with an autosomal dominant pattern of inheritance but incomplete penetrance. It is caused by a mutation in the CASP10 (caspase-10) gene that leads to defective Fas-induced apoptosis. Disruption of Fas-induced apoptosis impairs lymphocyte homeostasis and immune tolerance. Characteristic laboratory findings include an increase in circulating, double-negative (CD4-/CD8-) T cells in the setting of immune-mediated anemia, thrombocytopenia and neutropenia. Clinical signs present in childhood include fatigue, pallor, bruising, hepatosplenomegaly and chronic, non-malignant, non-infectious lymphadenopathy. The clinical course is influenced by a strong association with other autoimmune disorders and an increased risk for developing Hodgkin and non-Hodgkin lymphoma.
Last Evaluated: Aug 02, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:201209375
Autoimmune lymphoproliferative syndrome (ALPS), caused by defective lymphocyte homeostasis, is characterized by the following: Non-malignant lymphoproliferation (lymphadenopathy, hepatosplenomegaly with or without hypersplenism) that often improves with age. Autoimmune disease, mostly directed toward blood cells. Lifelong increased risk for both Hodgkin and non-Hodgkin lymphoma. In ALPS-FAS (the most common and best-characterized type of ALPS, associated with heterozygous germline pathogenic variants in FAS), non-malignant lymphoproliferation typically manifests in the first years of life, inexplicably waxes and wanes, and then often decreases without treatment in the second decade of life; in many affected individuals, however, neither splenomegaly nor the overall expansion of lymphocyte subsets in peripheral blood decreases. Although autoimmunity is often not present at the time of diagnosis or at the time of the most extensive lymphoproliferation, autoantibodies can be detected before autoimmune disease manifests clinically. In ALPS-FAS caused by homozygous or compound heterozygous (biallelic) pathogenic variants in FAS, severe lymphoproliferation occurs before, at, or shortly after birth, and usually results in death at an early age. ALPS-sFAS, resulting from somatic FAS pathogenic variants in selected cell populations, notably the alpha/beta double-negative T cells (a/ß-DNT cells), appears to be similar to ALPS-FAS resulting from heterozygous germline pathogenic variants in FAS, although lower incidence of splenectomy and lower lymphocyte counts have been reported in ALPS-sFAS and no cases of lymphoma have yet been published.
Last Evaluated: Aug 02, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 2:201209375
Low clinical importance, Likely protective — Reported to have a protective effect on breast cancer. If the lifetime risk of breast cancer is 12%, women with this variant may have a lower risk of 8-9% (30% less than average).
Benign/Likely benign
Hetero
Gene:
TOR1AIP1
Variant:
c.967+17A>G
rsID: rs17370826
Ref Allele: A
Alt Allele: G
Freq: 4.2017%uncommon
CADD: 2.659
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:179914071
Benign
Hetero
Gene:
PRKN
Variant:
c.*2492A>G
rsID: rs117341007
Ref Allele: T
Alt Allele: C
Freq: 4.22%uncommon
CADD: 1.285
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 6:161347607
Likely benign
Hetero
Gene:
DBT
Variant:
c.*5838G>A
rsID: rs79887429
Ref Allele: C
Alt Allele: T
Freq: 4.2248%uncommon
CADD: 7.231
ClinVar Submissions (1)
Maple syrup urine disease (MSUD) is classified as classic or intermediate. Twelve hours after birth, untreated neonates with classic MSUD have a maple syrup odor in cerumen; by 12-24 hours, elevated plasma concentrations of branched-chain amino acids (BCAAs) (leucine, isoleucine, and valine) and allo-isoleucine, as well as a generalized disturbance of plasma amino acid concentration ratios; by age two to three days, ketonuria, irritability, and poor feeding; by age four to five days, deepening encephalopathy manifesting as lethargy, intermittent apnea, opisthotonus, and stereotyped movements such as "fencing" and "bicycling." By age seven to ten days, coma and central respiratory failure may supervene. Individuals with intermediate MSUD have partial BCKAD enzyme deficiency that only manifests intermittently or responds to dietary thiamine therapy; these individuals can experience severe metabolic intoxication and encephalopathy during sufficient catabolic stress.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:100190417
Likely benign
Hetero
Gene:
MYO6
Variant:
c.1722C>T
(p.Asp574=)
rsID: rs11756446
Ref Allele: C
Alt Allele: T
Freq: 4.2248%uncommon
CADD: 5.956
ClinVar Submissions (5)
Last Evaluated: Aug 16, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:75866573
Last Evaluated: Aug 16, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:75866573
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Aug 16, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:75866573
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 16, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 6:75866573
Benign/Likely benign
Homo
Gene:
OTOF
Variant:
c.5655C>T
(p.Arg1885=)
rsID: rs45442103
Ref Allele: G
Alt Allele: A
Freq: 4.2256%uncommon
CADD: 14.03
ClinVar Submissions (5)
OTOF-related deafness (DFNB9 nonsyndromic hearing loss) is characterized by two phenotypes: prelingual nonsyndromic hearing loss and, less frequently, temperature-sensitive nonsyndromic auditory neuropathy (TS-NSAN). The nonsyndromic hearing loss is bilateral severe-to-profound congenital deafness. In the first one or two years of life, OTOF-related deafness can appear to be an auditory neuropathy based on electrophysiologic testing in which auditory brain stem responses (ABRs) are absent and otoacoustic emissions (OAEs) are present. However, with time OAEs disappear and electrophysiologic testing is more consistent with a cochlear defect. The distinction between auditory neuropathy and a cochlear defect is important as cochlear implants may be of marginal value in persons with auditory neuropathy but have been shown to be effective for individuals with OTOF-related deafness. TS-NSAN is characterized by normal-to-mild hearing loss in the absence of fever and significant hearing loss ranging from severe to profound in the presence of fever. When the fever resolves, hearing returns to normal.
Last Evaluated: Aug 10, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:26460909
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Aug 10, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:26460909
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 10, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:26460909
Benign
Hetero
Gene:
SPAST
Variant:
c.*98A>G
rsID: rs56272862
Ref Allele: A
Alt Allele: G
Freq: 4.2352%uncommon
CADD: 15.68
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:32154594
Likely benign
Hetero
Gene:
TPM1
Variant:
c.486T>C
(p.Tyr162=)
rsID: rs11558747
Ref Allele: T
Alt Allele: C
Freq: 4.2383%uncommon
CADD: 11.81
ClinVar Submissions (7)
Last Evaluated: Jan 23, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 15:63059674
Last Evaluated: Jan 23, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 15:63059674
A condition in which the myocardium is hypertrophied without an obvious cause. The hypertrophy is generally asymmetric and may be associated with obstruction of the ventricular outflow tract.
Last Evaluated: Jan 23, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 15:63059674
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jan 23, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 15:63059674
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jan 23, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 15:63059674
Benign/Likely benign
Hetero
Gene:
LAMC3
Variant:
c.3790C>T
(p.Arg1264Trp)
rsID: rs11244275
Ref Allele: C
Alt Allele: T
Freq: 4.2543%uncommon
CADD: 10.15
ClinVar Submissions (2)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Dec 21, 2013
Review Status: criteria provided, single submitter
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 9:131079161
Benign
Hetero
Gene:
HGF
Variant:
c.910G>A
(p.Glu304Lys)
rsID: rs5745687
Ref Allele: C
Alt Allele: T
Freq: 4.2583%uncommon
CADD: 16.75
ClinVar Submissions (5)
Last Evaluated: Oct 05, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:81729735
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Oct 05, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 7:81729735
Benign/Likely benign
Hetero
Gene:
ANK3
Variant:
c.8013C>T
(p.Ser2671=)
rsID: rs41274674
Ref Allele: G
Alt Allele: A
Freq: 4.2909%uncommon
CADD: 8.82
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: no assertion criteria provided
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 10:60072868
Likely benign
Hetero
Gene:
DSE
Variant:
c.101C>T
(p.Pro34Leu)
rsID: rs35548455
Ref Allele: C
Alt Allele: T
Freq: 4.3005%uncommon
CADD: 22.2
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Sep 30, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 6:116399351
Benign
Hetero
Gene:
GNRH1
Variant:
c.-471T>C
rsID: rs17790824
Ref Allele: A
Alt Allele: G
Freq: 4.3005%uncommon
CADD: 2.803
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Uncertain significance
Assembly: GRCh38
Chromosome/Position: 8:25423813
Conflicting/Uncertain
Hetero
Gene:
RYR2
Variant:
c.11776-21G>A
rsID: rs80013027
Ref Allele: G
Alt Allele: A
Freq: 4.3044%uncommon
CADD: 0.032
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:237778645
Likely benign
Hetero
Gene:
RFXANK
Variant:
c.213C>T
(p.Thr71=)
rsID: rs72997200
Ref Allele: C
Alt Allele: T
Freq: 4.3315%uncommon
CADD: 5.136
ClinVar Submissions (2)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 2
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 19:19196988
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 2
Clinical Significance: Conflicting interpretations of pathogenicity
Assembly: GRCh38
Chromosome/Position: 19:19196988
Conflicting/Uncertain
Hetero
Gene:
TJP2
Variant:
c.2004G>A
(p.Met668Ile)
rsID: rs34774441
Ref Allele: G
Alt Allele: A
Freq: 4.3403%uncommon
CADD: 25.3
ClinVar Submissions (4)
Last Evaluated: May 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 9:69236961
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: May 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 9:69236961
Benign/Likely benign
Hetero
Gene:
SGCA
Variant:
c.37+23G>A
rsID: rs79410682
Ref Allele: G
Alt Allele: A
Freq: 4.3538%uncommon
CADD: 5.399
ClinVar Submissions (2)
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Aug 11, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:50166100
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 11, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:50166100
Benign/Likely benign
Hetero
Gene:
POMGNT1
Variant:
c.1111-23C>T
rsID: rs2292486
Ref Allele: G
Alt Allele: A
Freq: 4.3697%uncommon
CADD: 10.12
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:46193238
Benign
Hetero
Gene:
IL36RN
Variant:
c.*828G>A
rsID: rs114189538
Ref Allele: G
Alt Allele: A
Freq: 4.3721%uncommon
CADD: 8.904
ClinVar Submissions (1)
Generalized pustular psoriasis (GPP) is a life-threatening disease characterized by sudden, repeated episodes of high-grade fever, generalized rash, and disseminated pustules, with hyperleukocytosis and elevated serum levels of C-reactive protein (123260) (summary by Marrakchi et al., 2011). GPP often presents in patients with existing or prior psoriasis vulgaris (PV; see 177900); however, GPP can develop without a history of PV (Sugiura et al., 2013). Palmoplantar pustulosis and acrodermatitis continua of Hallopeau represent acral forms of pustular psoriasis that have historically been grouped with GPP (summary by Setta-Kaffetzi et al., 2013). GPP in association with sterile multifocal osteomyelitis and periostitis (612852) is caused by mutation in the IL1RN gene (147679). Capon (2013) noted that the percentage of GPP patients reported to be negative for mutation in IL36RN ranges from 51 to 84%, indicative of genetic heterogeneity in the generalized pustular form of psoriasis. For a discussion of genetic heterogeneity of psoriasis, see PSORS1 (177900).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 2:113063505
Likely benign
Hetero
Gene:
SLC5A1
Variant:
c.152A>G
(p.Asn51Ser)
rsID: rs17683011
Ref Allele: A
Alt Allele: G
Freq: 4.3801%uncommon
CADD: 18.88
ClinVar Submissions (2)
Glucose/galactose malabsorption (GGM) is a rare autosomal recessive disorder caused by a defect in glucose and galactose transport across the intestinal brush border. Patients with GGM present with neonatal onset of severe life-threatening watery diarrhea and dehydration. If diagnosed and treated properly, patients can fully recover and show normal growth and development (summary by Xin and Wang, 2011).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 22:32049959
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 22:32049959
Benign/Likely benign
Hetero
Gene:
SLC5A1
Variant:
c.1231G>A
(p.Ala411Thr)
rsID: rs17683430
Ref Allele: G
Alt Allele: A
Freq: 4.3825%uncommon
CADD: 16.94
ClinVar Submissions (2)
Glucose/galactose malabsorption (GGM) is a rare autosomal recessive disorder caused by a defect in glucose and galactose transport across the intestinal brush border. Patients with GGM present with neonatal onset of severe life-threatening watery diarrhea and dehydration. If diagnosed and treated properly, patients can fully recover and show normal growth and development (summary by Xin and Wang, 2011).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 22:32091713
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 22:32091713
Benign/Likely benign
Hetero
Gene:
TOR1AIP1
Variant:
c.882A>C
(p.Gln294His)
rsID: rs17279712
Ref Allele: A
Alt Allele: C
Freq: 4.3841%uncommon
CADD: 0.322
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:179908645
Benign
Hetero
Gene:
SLC5A1
Variant:
c.1275C>T
(p.Ala425=)
rsID: rs17683448
Ref Allele: C
Alt Allele: T
Freq: 4.3873%uncommon
CADD: 0.997
ClinVar Submissions (2)
Glucose/galactose malabsorption (GGM) is a rare autosomal recessive disorder caused by a defect in glucose and galactose transport across the intestinal brush border. Patients with GGM present with neonatal onset of severe life-threatening watery diarrhea and dehydration. If diagnosed and treated properly, patients can fully recover and show normal growth and development (summary by Xin and Wang, 2011).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 22:32091757
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 22:32091757
Benign/Likely benign
Hetero
Gene:
SLC5A1
Variant:
c.1938C>T
(p.Asn646=)
rsID: rs33954397
Ref Allele: C
Alt Allele: T
Freq: 4.3873%uncommon
CADD: 9.297
ClinVar Submissions (2)
Glucose/galactose malabsorption (GGM) is a rare autosomal recessive disorder caused by a defect in glucose and galactose transport across the intestinal brush border. Patients with GGM present with neonatal onset of severe life-threatening watery diarrhea and dehydration. If diagnosed and treated properly, patients can fully recover and show normal growth and development (summary by Xin and Wang, 2011).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 22:32110156
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 22:32110156
Benign/Likely benign
Hetero
Gene:
SLC5A1
Variant:
c.1836A>G
(p.Leu612=)
rsID: rs17683704
Ref Allele: A
Alt Allele: G
Freq: 4.3905%uncommon
CADD: 10.73
ClinVar Submissions (2)
Glucose/galactose malabsorption (GGM) is a rare autosomal recessive disorder caused by a defect in glucose and galactose transport across the intestinal brush border. Patients with GGM present with neonatal onset of severe life-threatening watery diarrhea and dehydration. If diagnosed and treated properly, patients can fully recover and show normal growth and development (summary by Xin and Wang, 2011).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 22:32110054
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 22:32110054
Benign/Likely benign
Hetero
Gene:
SLC5A1
Variant:
c.1845C>G
(p.His615Gln)
rsID: rs33954001
Ref Allele: C
Alt Allele: G
Freq: 4.3905%uncommon
CADD: 8.425
ClinVar Submissions (2)
Glucose/galactose malabsorption (GGM) is a rare autosomal recessive disorder caused by a defect in glucose and galactose transport across the intestinal brush border. Patients with GGM present with neonatal onset of severe life-threatening watery diarrhea and dehydration. If diagnosed and treated properly, patients can fully recover and show normal growth and development (summary by Xin and Wang, 2011).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 22:32110063
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 22:32110063
Benign/Likely benign
Hetero
Gene:
SLC5A1
Variant:
c.*1940G>A
rsID: rs117112619
Ref Allele: G
Alt Allele: A
Freq: 4.3952%uncommon
CADD: 2.069
ClinVar Submissions (1)
Glucose/galactose malabsorption (GGM) is a rare autosomal recessive disorder caused by a defect in glucose and galactose transport across the intestinal brush border. Patients with GGM present with neonatal onset of severe life-threatening watery diarrhea and dehydration. If diagnosed and treated properly, patients can fully recover and show normal growth and development (summary by Xin and Wang, 2011).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 22:32112153
Likely benign
Hetero
Gene:
ADAMTS13
Variant:
c.173-18C>T
rsID: rs35410697
Ref Allele: C
Alt Allele: T
Freq: 4.4024%uncommon
CADD: 1.195
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 9:133424303
Benign
Hetero
Gene:
GATA3
Variant:
c.621C>T
(p.Ala207=)
rsID: rs2229359
Ref Allele: C
Alt Allele: T
Freq: 4.4088%uncommon
CADD: 14.33
ClinVar Submissions (3)
A condition characterized by hypoparathyroidism, sensorineural deafness, and renal failure. It is related to autosomal dominant inactivating mutation(s) in GATA3, encoding a transcription factor important for the embryonic development of the parathyroid gland, the auditory stem, and the kidneys.
Last Evaluated: May 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 10:8058684
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: May 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 10:8058684
Benign
Hetero
Gene:
DUOX2
Variant:
c.2944C>G
(p.Pro982Ala)
rsID: rs61730030
Ref Allele: G
Alt Allele: C
Freq: 4.4167%uncommon
CADD: 0.96
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 15:45100816
Benign
Hetero
Gene:
CACNB4
Variant:
c.*890G>C
rsID: rs78697588
Ref Allele: C
Alt Allele: G
Freq: 4.4215%uncommon
CADD: 11.22
ClinVar Submissions (1)
Periodic spells of incoordination and imbalance, that is, episodes of ataxia typically lasting from 10 minutes to several hours or days.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:151838229
Juvenile myoclonic epilepsy is a subtype of idiopathic generalized epilepsy (EIG; see 600669) affecting up to 26% of all individuals with EIG. Individuals with JME have afebrile seizures only, with onset in adolescence of myoclonic jerks. Myoclonic jerks occur usually in the morning (Janz and Durner, 1997). Genetic Heterogeneity of Juvenile Myoclonic Seizures Susceptibility to EJM can be conferred by variation in several other genes: EJM5 (611136), by variation in the GABRA1 gene (137160) on 5q34; EJM6 (see 607682), by variation in the CACNB4 gene (601949) on 2q23; EJM7 (see 613060), by variation in the GABRD gene (137163) on 1p36; EJM8 (see 607628), by variation in the CLCN2 gene (600570) on 3q27; and EJM10 (617924), by variation in the ICK gene (612325) on chromosome 6p12. In addition, EJM loci have been identified by linkage analysis: EJM2 (see 604827) on 15q14, EJM3 (608816) on 6p21, EJM4 (611364) on 5q12-q14, and EJM9 (614280) on 2q33-q36.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:151838229
Benign
Hetero
Gene:
CLDN14
Variant:
c.11C>T
(p.Thr4Met)
rsID: rs113831133
Ref Allele: G
Alt Allele: A
Freq: 4.439%uncommon
CADD: 15.54
ClinVar Submissions (5)
Last Evaluated: Dec 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 21:36461685
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Dec 07, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 21:36461685
Benign/Likely benign
Hetero
Gene:
MMAB
Variant:
c.*1409G>A
rsID: rs72650177
Ref Allele: C
Alt Allele: T
Freq: 4.4478%uncommon
CADD: 4.567
ClinVar Submissions (1)
Isolated methylmalonic acidemia/aciduria, the topic of this GeneReview, is caused by complete or partial deficiency of the enzyme methylmalonyl-CoA mutase (mut0 enzymatic subtype or mut– enzymatic subtype, respectively), a defect in the transport or synthesis of its cofactor, adenosyl-cobalamin (cblA, cblB, or cblD-MMA), or deficiency of the enzyme methylmalonyl-CoA epimerase. Onset of the manifestations of isolated methylmalonic acidemia/aciduria ranges from the neonatal period to adulthood. All phenotypes are characterized by periods of relative health and intermittent metabolic decompensation, usually associated with intercurrent infections and stress. In the neonatal period the disease can present with lethargy, vomiting, hypotonia, hypothermia, respiratory distress, severe ketoacidosis, hyperammonemia, neutropenia, and thrombocytopenia and can result in death within the first four weeks of life. In the infantile/non-B12-responsive phenotype, infants are normal at birth, but develop lethargy, vomiting, dehydration, failure to thrive, hepatomegaly, hypotonia, and encephalopathy within a few weeks to months of age. An intermediate B12-responsive phenotype can occasionally be observed in neonates, but is usually observed in the first months or years of life; affected children exhibit anorexia, failure to thrive, hypotonia, and developmental delay, and sometimes have protein aversion and/or vomiting and lethargy after protein intake. Atypical and "benign"/adult methylmalonic acidemia phenotypes are associated with increased, albeit mild, urinary excretion of methylmalonate. Major secondary complications of methylmalonic acidemia include: intellectual impairment (variable); tubulointerstitial nephritis with progressive renal failure; "metabolic stroke" (acute and chronic basal ganglia injury) causing a disabling movement disorder with choreoathetosis, dystonia, and para/quadriparesis; pancreatitis; growth failure; functional immune impairment; and optic nerve atrophy.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 12:109555619
Likely benign
Hetero
Gene:
ARHGAP31
Variant:
c.*2743C>A
rsID: rs78013508
Ref Allele: C
Alt Allele: A
Freq: 4.4757%uncommon
CADD: 0.843
ClinVar Submissions (1)
Adams-Oliver syndrome (AOS) is characterized by aplasia cutis congenita (ACC) of the scalp and terminal transverse limb defects (TTLD). ACC lesions usually occur in the midline of the parietal or occipital regions, but can also occur on the abdomen or limbs. At birth, an ACC lesion may already have the appearance of a healed scar. ACC lesions less than 5 cm often involve only the skin and almost always heal over a period of months; larger lesions are more likely to involve the skull and possibly the dura, and are at greater risk for complications, which can include infection, hemorrhage, or thrombosis, and can result in death. The limb defects range from mild (unilateral or bilateral short distal phalanges) to severe (complete absence of all toes or fingers, feet or hands, or more, often resembling an amputation). The lower extremities are almost always more severely affected than the upper extremities. Additional major features frequently include cardiovascular malformations/dysfunction (23%), brain anomalies, and less frequently renal, liver, and eye anomalies.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 3:119419007
Likely benign
Hetero
Gene:
DBT
Variant:
c.*4395G>A
rsID: rs79471979
Ref Allele: C
Alt Allele: T
Freq: 4.4964%uncommon
CADD: 0.375
ClinVar Submissions (1)
Maple syrup urine disease (MSUD) is classified as classic or intermediate. Twelve hours after birth, untreated neonates with classic MSUD have a maple syrup odor in cerumen; by 12-24 hours, elevated plasma concentrations of branched-chain amino acids (BCAAs) (leucine, isoleucine, and valine) and allo-isoleucine, as well as a generalized disturbance of plasma amino acid concentration ratios; by age two to three days, ketonuria, irritability, and poor feeding; by age four to five days, deepening encephalopathy manifesting as lethargy, intermittent apnea, opisthotonus, and stereotyped movements such as "fencing" and "bicycling." By age seven to ten days, coma and central respiratory failure may supervene. Individuals with intermediate MSUD have partial BCKAD enzyme deficiency that only manifests intermittently or responds to dietary thiamine therapy; these individuals can experience severe metabolic intoxication and encephalopathy during sufficient catabolic stress.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:100191860
Likely benign
Hetero
Gene:
RGS9BP
Variant:
c.39C>G
(p.Leu13=)
rsID: rs3826926
Ref Allele: C
Alt Allele: G
Freq: 4.5043%uncommon
CADD: 21.4
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Nov 17, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 19:32676302
Benign
Hetero
Gene:
TSEN54
Variant:
c.1447C>G
(p.Pro483Ala)
rsID: rs62088470
Ref Allele: C
Alt Allele: G
Freq: 4.5075%uncommon
CADD: 26.4
ClinVar Submissions (4)
Pontocerebellar hypoplasia is a group of related conditions that affect the development of the brain. The term "pontocerebellar" refers to the pons and the cerebellum, which are the brain structures that are most severely affected in many forms of this disorder. The pons is located at the base of the brain in an area called the brainstem, where it transmits signals between the cerebellum and the rest of the brain. The cerebellum, which is located at the back of the brain, normally coordinates movement. The term "hypoplasia" refers to the underdevelopment of these brain regions.Pontocerebellar hypoplasia also causes impaired growth of other parts of the brain, leading to an unusually small head size (microcephaly). This microcephaly is usually not apparent at birth but becomes noticeable as brain growth continues to be slow in infancy and early childhood.Researchers have described at least ten types of pontocerebellar hypoplasia. All forms of this condition are characterized by impaired brain development, delayed development overall, problems with movement, and intellectual disability. The brain abnormalities are usually present at birth, and in some cases they can be detected before birth. Many children with pontocerebellar hypoplasia live only into infancy or childhood, although some affected individuals have lived into adulthood.The two major forms of pontocerebellar hypoplasia are designated as type 1 (PCH1) and type 2 (PCH2). In addition to the brain abnormalities described above, PCH1 causes problems with muscle movement resulting from a loss of specialized nerve cells called motor neurons in the spinal cord, similar to another genetic disorder known as spinal muscular atrophy. Individuals with PCH1 also have very weak muscle tone (hypotonia), joint deformities called contractures, vision impairment, and breathing and feeding problems that are evident from early infancy.Common features of PCH2 include a lack of voluntary motor skills (such as grasping objects, sitting, or walking), problems with swallowing (dysphagia), and an absence of communication, including speech. Affected children typically develop temporary jitteriness (generalized clonus) in early infancy, abnormal patterns of movement described as chorea or dystonia, and stiffness (spasticity). Many also have impaired vision and seizures.The other forms of pontocerebellar hypoplasia, designated as type 3 (PCH3) through type 10 (PCH10), appear to be rare and have each been reported in only a small number of individuals. Because the different types have overlapping features, and some are caused by mutations in the same genes, researchers have proposed that the types be considered as a spectrum instead of distinct conditions.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:75524278
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 17:75524278
Benign/Likely benign
Hetero
Gene:
SLC33A1
Variant:
c.*1141A>T
rsID: rs77664705
Ref Allele: T
Alt Allele: A
Freq: 4.5083%uncommon
CADD: 0.08
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 3:155827069
Likely benign
Hetero
Gene:
INSR
Variant:
c.2997C>T
(p.Tyr999=)
rsID: rs1799815
Ref Allele: G
Alt Allele: A
Freq: 4.5235%uncommon
CADD: 1.735
ClinVar Submissions (2)
Type A insulin resistance syndrome is a rare disorder characterized by severe insulin resistance, a condition in which the body's tissues and organs do not respond properly to the hormone insulin. Insulin normally helps regulate blood sugar levels by controlling how much sugar (in the form of glucose) is passed from the bloodstream into cells to be used as energy. In people with type A insulin resistance syndrome, insulin resistance impairs blood sugar regulation and ultimately leads to a condition called diabetes mellitus, in which blood sugar levels can become dangerously high.Severe insulin resistance also underlies the other signs and symptoms of type A insulin resistance syndrome. In affected females, the major features of the condition become apparent in adolescence. Many affected females do not begin menstruation by age 16 (primary amenorrhea) or their periods may be light and irregular (oligomenorrhea). They develop cysts on the ovaries and excessive body hair growth (hirsutism). Most affected females also develop a skin condition called acanthosis nigricans, in which the skin in body folds and creases becomes thick, dark, and velvety. Unlike most people with insulin resistance, females with type A insulin resistance syndrome are usually not overweight.The features of type A insulin resistance syndrome are more subtle in affected males. Some males have low blood sugar (hypoglycemia) as the only sign; others may also have acanthosis nigricans. In many cases, males with this condition come to medical attention only when they develop diabetes mellitus in adulthood.Type A insulin resistance syndrome is one of a group of related conditions described as inherited severe insulin resistance syndromes. These disorders, which also include Donohue syndrome and Rabson-Mendenhall syndrome, are considered part of a spectrum. Type A insulin resistance syndrome represents the mildest end of the spectrum: its features often do not become apparent until puberty or later, and it is generally not life-threatening.
Last Evaluated: Jan 17, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 19:7125508
INSR-related severe syndromic insulin resistance comprises a phenotypic spectrum that is a continuum from the severe phenotype Donohue syndrome (DS) (also known as leprechaunism) to the milder phenotype Rabson-Mendenhall syndrome (RMS). DS at the severe end of the spectrum is characterized by severe insulin resistance (hyperinsulinemia with associated fasting hypoglycemia and postprandial hyperglycemia), severe prenatal growth restriction and postnatal growth failure, hypotonia and developmental delay, characteristic facies, and organomegaly involving heart, kidneys, liver, spleen, and ovaries. Death usually occurs before age one year. RMS at the milder end of the spectrum is characterized by severe insulin resistance that, although not as severe as that of DS, is nonetheless accompanied by fluctuations in blood glucose levels, diabetic ketoacidosis, and – in the second decade – microvascular complications. Findings can range from severe growth delay and intellectual disability to normal growth and development. Facial features can be milder than those of DS. Complications of longstanding hyperglycemia are the most common cause of death. While death usually occurs in the second decade, some affected individuals live longer.
Last Evaluated: Jan 17, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 19:7125508
INSR-related severe syndromic insulin resistance comprises a phenotypic spectrum that is a continuum from the severe phenotype Donohue syndrome (DS) (also known as leprechaunism) to the milder phenotype Rabson-Mendenhall syndrome (RMS). DS at the severe end of the spectrum is characterized by severe insulin resistance (hyperinsulinemia with associated fasting hypoglycemia and postprandial hyperglycemia), severe prenatal growth restriction and postnatal growth failure, hypotonia and developmental delay, characteristic facies, and organomegaly involving heart, kidneys, liver, spleen, and ovaries. Death usually occurs before age one year. RMS at the milder end of the spectrum is characterized by severe insulin resistance that, although not as severe as that of DS, is nonetheless accompanied by fluctuations in blood glucose levels, diabetic ketoacidosis, and – in the second decade – microvascular complications. Findings can range from severe growth delay and intellectual disability to normal growth and development. Facial features can be milder than those of DS. Complications of longstanding hyperglycemia are the most common cause of death. While death usually occurs in the second decade, some affected individuals live longer.
Last Evaluated: Jan 17, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 19:7125508
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jan 17, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 19:7125508
Benign
Hetero
Gene:
MERTK
Variant:
c.61+19G>A
rsID: rs115821982
Ref Allele: G
Alt Allele: A
Freq: 4.5322%uncommon
CADD: 7.017
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Apr 13, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:111898815
Benign
Hetero
Gene:
GAA
Variant:
c.1888+21G>A
rsID: rs2304837
Ref Allele: G
Alt Allele: A
Freq: 4.5378%uncommon
CADD: 4.656
ClinVar Submissions (3)
Pompe disease is classified by age of onset, organ involvement, severity, and rate of progression. Infantile-onset Pompe disease (IOPD; individuals with onset before age 12 months with cardiomyopathy) may be apparent in utero but more typically onset is at the median age of four months with hypotonia, generalized muscle weakness, feeding difficulties, failure to thrive, respiratory distress, and hypertrophic cardiomyopathy. Without treatment by enzyme replacement therapy (ERT), IOPD commonly results in death by age two years from progressive left ventricular outflow obstruction and respiratory insufficiency. Late-onset Pompe disease (LOPD; including: (a) individuals with onset before age 12 months without cardiomyopathy; and (b) all individuals with onset after age 12 months) is characterized by proximal muscle weakness and respiratory insufficiency; clinically significant cardiac involvement is uncommon.
Last Evaluated: Dec 08, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 17:80112732
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Dec 08, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 17:80112732
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Dec 08, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 17:80112732
Benign
Hetero
Gene:
TTR
Variant:
c.76G>A
(p.Gly26Ser)
rsID: rs1800458
Ref Allele: G
Alt Allele: A
Freq: 4.541%uncommon
CADD: 7.756
ClinVar Submissions (8)
Last Evaluated: Jun 14, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 18:31592902
OMIM Allelic Variant: 176300.0036
Last Evaluated: Jun 14, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 18:31592902
OMIM Allelic Variant: 176300.0036
Last Evaluated: Jun 14, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 18:31592902
OMIM Allelic Variant: 176300.0036
Last Evaluated: Jun 14, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 18:31592902
OMIM Allelic Variant: 176300.0036
Benign
Hetero
Gene:
GAA
Variant:
c.2065G>A
(p.Glu689Lys)
rsID: rs1800309
Ref Allele: G
Alt Allele: A
Freq: 4.5426%uncommon
CADD: 18.3
ClinVar Submissions (8)
Last Evaluated: Jul 09, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 8
Clinical Significance: Conflicting interpretations of pathogenicity, other
Assembly: GRCh38
Chromosome/Position: 17:80113242
OMIM Allelic Variant: 606800.0011
Last Evaluated: Jul 09, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 8
Clinical Significance: Conflicting interpretations of pathogenicity, other
Assembly: GRCh38
Chromosome/Position: 17:80113242
OMIM Allelic Variant: 606800.0011
Last Evaluated: Jul 09, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 8
Clinical Significance: Conflicting interpretations of pathogenicity, other
Assembly: GRCh38
Chromosome/Position: 17:80113242
OMIM Allelic Variant: 606800.0011
Last Evaluated: Jul 09, 2018
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 8
Clinical Significance: Conflicting interpretations of pathogenicity, other
Assembly: GRCh38
Chromosome/Position: 17:80113242
OMIM Allelic Variant: 606800.0011
Low clinical importance, Uncertain benign — This is also known as the GAA*4 allozyme is frequent in the Asian population and appears to have somewhat reduced enzyme activity. Kroos et al. rule out pathogenic effect.
Clinically Significant Conflicting/Uncertain
Hetero
Gene:
MVK
Variant:
c.405G>A
(p.Ser135=)
rsID: rs34368092
Ref Allele: G
Alt Allele: A
Freq: 4.5521%uncommon
CADD: 0.154
ClinVar Submissions (6)
Mevalonate kinase deficiency is a condition characterized by recurrent episodes of fever, which typically begin during infancy. Each episode of fever lasts about 3 to 6 days, and the frequency of the episodes varies among affected individuals. In childhood the fevers seem to be more frequent, occurring as often as 25 times a year, but as the individual gets older the episodes occur less often.Mevalonate kinase deficiency has additional signs and symptoms, and the severity depends on the type of the condition. There are two types of mevalonate kinase deficiency: a less severe type called hyperimmunoglobulinemia D syndrome (HIDS) and a more severe type called mevalonic aciduria (MVA).During episodes of fever, people with HIDS typically have enlargement of the lymph nodes (lymphadenopathy), abdominal pain, joint pain, diarrhea, skin rashes, and headache. Occasionally they will have painful sores called aphthous ulcers around their mouth. In females, these may also occur around the vagina. Rarely, people with HIDS develop a buildup of protein deposits (amyloidosis) in the kidneys that can lead to kidney failure. Fever episodes in individuals with HIDS can be triggered by vaccinations, surgery, injury, or stress. Most people with HIDS have abnormally high levels of immune system proteins called immunoglobulin D (IgD) and immunoglobulin A (IgA) in the blood. It is unclear why some people with HIDS have high levels of IgD and IgA and some do not. Elevated levels of these immunoglobulins do not appear to cause any signs or symptoms. Individuals with HIDS do not have any signs and symptoms of the condition between fever episodes and typically have a normal life expectancy.People with MVA have signs and symptoms of the condition at all times, not just during episodes of fever. Affected children have developmental delay, problems with movement and balance (ataxia), recurrent seizures (epilepsy), progressive problems with vision, and failure to gain weight and grow at the expected rate (failure to thrive). Individuals with MVA typically have an unusually small, elongated head. In childhood or adolescence, affected individuals may develop eye problems such as inflammation of the eye (uveitis), a blue tint in the white part of the eye (blue sclera), an eye disorder called retinitis pigmentosa that causes vision loss, or clouding of the lens of the eye (cataracts). Affected adults may have short stature and may develop muscle weakness (myopathy) later in life. During fever episodes, people with MVA may have an enlarged liver and spleen (hepatosplenomegaly), lymphadenopathy, abdominal pain, diarrhea, and skin rashes. Children with MVA who are severely affected with multiple problems may live only into early childhood; mildly affected individuals may have a normal life expectancy.
Last Evaluated: Aug 21, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:109581428
Mevalonate kinase deficiency is a condition characterized by recurrent episodes of fever, which typically begin during infancy. Each episode of fever lasts about 3 to 6 days, and the frequency of the episodes varies among affected individuals. In childhood the fevers seem to be more frequent, occurring as often as 25 times a year, but as the individual gets older the episodes occur less often.Mevalonate kinase deficiency has additional signs and symptoms, and the severity depends on the type of the condition. There are two types of mevalonate kinase deficiency: a less severe type called hyperimmunoglobulinemia D syndrome (HIDS) and a more severe type called mevalonic aciduria (MVA).During episodes of fever, people with HIDS typically have enlargement of the lymph nodes (lymphadenopathy), abdominal pain, joint pain, diarrhea, skin rashes, and headache. Occasionally they will have painful sores called aphthous ulcers around their mouth. In females, these may also occur around the vagina. Rarely, people with HIDS develop a buildup of protein deposits (amyloidosis) in the kidneys that can lead to kidney failure. Fever episodes in individuals with HIDS can be triggered by vaccinations, surgery, injury, or stress. Most people with HIDS have abnormally high levels of immune system proteins called immunoglobulin D (IgD) and immunoglobulin A (IgA) in the blood. It is unclear why some people with HIDS have high levels of IgD and IgA and some do not. Elevated levels of these immunoglobulins do not appear to cause any signs or symptoms. Individuals with HIDS do not have any signs and symptoms of the condition between fever episodes and typically have a normal life expectancy.People with MVA have signs and symptoms of the condition at all times, not just during episodes of fever. Affected children have developmental delay, problems with movement and balance (ataxia), recurrent seizures (epilepsy), progressive problems with vision, and failure to gain weight and grow at the expected rate (failure to thrive). Individuals with MVA typically have an unusually small, elongated head. In childhood or adolescence, affected individuals may develop eye problems such as inflammation of the eye (uveitis), a blue tint in the white part of the eye (blue sclera), an eye disorder called retinitis pigmentosa that causes vision loss, or clouding of the lens of the eye (cataracts). Affected adults may have short stature and may develop muscle weakness (myopathy) later in life. During fever episodes, people with MVA may have an enlarged liver and spleen (hepatosplenomegaly), lymphadenopathy, abdominal pain, diarrhea, and skin rashes. Children with MVA who are severely affected with multiple problems may live only into early childhood; mildly affected individuals may have a normal life expectancy.
Last Evaluated: Aug 21, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:109581428
Mevalonic aciduria, the first recognized defect in the biosynthesis of cholesterol and isoprenoids, is a consequence of a deficiency of mevalonate kinase (ATP:mevalonate 5-phosphotransferase; EC 2.7.1.36). Mevalonic acid accumulates because of failure of conversion to 5-phosphomevalonic acid, which is catalyzed by mevalonate kinase. Mevalonic acid is synthesized from 3-hydroxy-3-methylglutaryl-CoA, a reaction catalyzed by HMG-CoA reductase (142910). Mevalonic aciduria is characterized by dysmorphology, psychomotor retardation, progressive cerebellar ataxia, and recurrent febrile crises, usually manifesting in early infancy, accompanied by hepatosplenomegaly, lymphadenopathy, arthralgia, and skin rash. The febrile crises are similar to those observed in hyperimmunoglobulinemia D and to periodic fever syndrome (HIDS; 260920), which is also caused by mutation in the MVK gene (summary by Prietsch et al., 2003).
Last Evaluated: Aug 21, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:109581428
Mevalonic aciduria, the first recognized defect in the biosynthesis of cholesterol and isoprenoids, is a consequence of a deficiency of mevalonate kinase (ATP:mevalonate 5-phosphotransferase; EC 2.7.1.36). Mevalonic acid accumulates because of failure of conversion to 5-phosphomevalonic acid, which is catalyzed by mevalonate kinase. Mevalonic acid is synthesized from 3-hydroxy-3-methylglutaryl-CoA, a reaction catalyzed by HMG-CoA reductase (142910). Mevalonic aciduria is characterized by dysmorphology, psychomotor retardation, progressive cerebellar ataxia, and recurrent febrile crises, usually manifesting in early infancy, accompanied by hepatosplenomegaly, lymphadenopathy, arthralgia, and skin rash. The febrile crises are similar to those observed in hyperimmunoglobulinemia D and to periodic fever syndrome (HIDS; 260920), which is also caused by mutation in the MVK gene (summary by Prietsch et al., 2003).
Last Evaluated: Aug 21, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:109581428
Porokeratosis is a rare skin disorder characterized by one or more annular plaques with a surrounding raised horny border that spreads centrifugally. Variants of porokeratosis have been described that differ in morphologic shapes, distribution, and clinical course (Schamroth et al., 1997). However, as noted by Sybert (2010), several families with expression of more than one variant of porokeratosis among members, and individuals expressing more than one variant, have been reported, suggesting that the distinctions among these variants may be artificial. Mutations in the MVK gene have been found to cause multiple types of porokeratosis, which have been described as disseminated superficial actinic porokeratosis (DSAP), nonactinic disseminated superficial porokeratosis (DSP), porokeratosis of Mibelli, giant plaque of porokeratosis ptychotropica, hyperkeratotic porokeratosis, and linear porokeratosis. The preferred title of this entry was formerly 'Porokeratosis 3, Disseminated Superficial Actinic Type; POROK3.' Disseminated superficial actinic porokeratosis is the most common subtype of porokeratosis. It is characterized by multiple small, annular, anhidrotic, keratotic lesions that are located predominantly on sun-exposed areas of the skin, such as the face, neck, and distal limbs. The lesions typically begin to develop in adolescence and reach near-complete penetrance by the third or fourth decade of life (summary by Wu et al., 2004 and Zhang et al., 2012). For a discussion of genetic heterogeneity of porokeratosis, see 175800.
Last Evaluated: Aug 21, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:109581428
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Aug 21, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:109581428
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 21, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:109581428
Benign/Likely benign
Hetero
Gene:
KCNA1
Variant:
c.*1524A>G
rsID: rs79357862
Ref Allele: A
Alt Allele: G
Freq: 4.5529%uncommon
CADD: 16.64
ClinVar Submissions (1)
Periodic spells of incoordination and imbalance, that is, episodes of ataxia typically lasting from 10 minutes to several hours or days.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 12:4914390
A disorder characterized by involuntary and irregular muscle contractions not associated with muscle weakness or atrophy. It most often affects facial muscles. It may be localized or generalized.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 12:4914390
Benign
Hetero
Gene:
GLRB
Variant:
c.948T>C
(p.Leu316=)
rsID: rs1801154
Ref Allele: T
Alt Allele: C
Freq: 4.5657%uncommon
CADD: 1.98
ClinVar Submissions (1)
Hereditary hyperekplexia (HPX) is characterized by generalized stiffness immediately after birth that normalizes during the first years of life; excessive startle reflex (eye blinking and a flexor spasm of the trunk) to unexpected (particularly auditory) stimuli; and a short period of generalized stiffness following the startle response during which voluntary movements are impossible. Exaggerated head-retraction reflex (HRR) consisting of extension of the head followed by violent flexor spasms of limbs and neck muscles elicited by tapping the tip of the nose is observed in most children. Other findings include periodic limb movements in sleep (PLMS) and hypnagogic (occurring when falling asleep) myoclonus. Sudden infant death (SIDS) has been reported. Intellect is usually normal; mild intellectual disability may occur.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 4:157152761
Benign
Hetero
Gene:
DUOX2
Variant:
c.2102G>A
(p.Arg701Gln)
rsID: rs113400262
Ref Allele: C
Alt Allele: T
Freq: 4.5744%uncommon
CADD: 13.46
ClinVar Submissions (2)
Congenital hypothyroidism is a partial or complete loss of function of the thyroid gland (hypothyroidism) that affects infants from birth (congenital). The thyroid gland is a butterfly-shaped tissue in the lower neck. It makes iodine-containing hormones that play an important role in regulating growth, brain development, and the rate of chemical reactions in the body (metabolism). People with congenital hypothyroidism have lower-than-normal levels of these important hormones.Congenital hypothyroidism occurs when the thyroid gland fails to develop or function properly. In 80 to 85 percent of cases, the thyroid gland is absent, severely reduced in size (hypoplastic), or abnormally located. These cases are classified as thyroid dysgenesis. In the remainder of cases, a normal-sized or enlarged thyroid gland (goiter) is present, but production of thyroid hormones is decreased or absent. Most of these cases occur when one of several steps in the hormone synthesis process is impaired; these cases are classified as thyroid dyshormonogenesis. Less commonly, reduction or absence of thyroid hormone production is caused by impaired stimulation of the production process (which is normally done by a structure at the base of the brain called the pituitary gland), even though the process itself is unimpaired. These cases are classified as central (or pituitary) hypothyroidism.Signs and symptoms of congenital hypothyroidism result from the shortage of thyroid hormones. Affected babies may show no features of the condition, although some babies with congenital hypothyroidism are less active and sleep more than normal. They may have difficulty feeding and experience constipation. If untreated, congenital hypothyroidism can lead to intellectual disability and slow growth. In the United States and many other countries, all hospitals test newborns for congenital hypothyroidism. If treatment begins in the first two weeks after birth, infants usually develop normally.Congenital hypothyroidism can also occur as part of syndromes that affect other organs and tissues in the body. These forms of the condition are described as syndromic. Some common forms of syndromic hypothyroidism include Pendred syndrome, Bamforth-Lazarus syndrome, and brain-lung-thyroid syndrome.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 15:45106171
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 15:45106171
Benign/Likely benign
Hetero
Gene:
AP3B1
Variant:
c.1683C>T
(p.Leu561=)
rsID: rs17192146
Ref Allele: G
Alt Allele: A
Freq: 4.5864%uncommon
CADD: 6.908
ClinVar Submissions (3)
Hermansky-Pudlak syndrome (HPS) is characterized by oculocutaneous albinism, a bleeding diathesis, and, in some individuals, pulmonary fibrosis, granulomatous colitis, or immunodeficiency. Ocular findings include reduced iris pigment with iris transillumination, reduced retinal pigment, foveal hypoplasia with significant reduction in visual acuity (usually in the range of 20/50 to 20/400), nystagmus, and increased crossing of the optic nerve fibers. Hair color ranges from white to brown; skin color ranges from white to olive and is usually a shade lighter than that of other family members. The bleeding diathesis can result in variable bruising, epistaxis, gingival bleeding, postpartum hemorrhage, colonic bleeding, and prolonged bleeding with menses or after tooth extraction, circumcision, and other surgeries. Pulmonary fibrosis, a restrictive lung disease, typically causes symptoms in the early thirties and can progress to death within a decade. Granulomatous colitis is severe in about 15% of affected individuals. Neutropenia and/or immune defects occur primarily in individuals with pathogenic variants in AP3B1 and AP3D1.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 5:78129275
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 5:78129275
Benign/Likely benign
Hetero
Gene:
MMAB
Variant:
c.*1657G>A
rsID: rs111869218
Ref Allele: C
Alt Allele: T
Freq: 4.5927%uncommon
CADD: 1.725
ClinVar Submissions (1)
Isolated methylmalonic acidemia/aciduria, the topic of this GeneReview, is caused by complete or partial deficiency of the enzyme methylmalonyl-CoA mutase (mut0 enzymatic subtype or mut– enzymatic subtype, respectively), a defect in the transport or synthesis of its cofactor, adenosyl-cobalamin (cblA, cblB, or cblD-MMA), or deficiency of the enzyme methylmalonyl-CoA epimerase. Onset of the manifestations of isolated methylmalonic acidemia/aciduria ranges from the neonatal period to adulthood. All phenotypes are characterized by periods of relative health and intermittent metabolic decompensation, usually associated with intercurrent infections and stress. In the neonatal period the disease can present with lethargy, vomiting, hypotonia, hypothermia, respiratory distress, severe ketoacidosis, hyperammonemia, neutropenia, and thrombocytopenia and can result in death within the first four weeks of life. In the infantile/non-B12-responsive phenotype, infants are normal at birth, but develop lethargy, vomiting, dehydration, failure to thrive, hepatomegaly, hypotonia, and encephalopathy within a few weeks to months of age. An intermediate B12-responsive phenotype can occasionally be observed in neonates, but is usually observed in the first months or years of life; affected children exhibit anorexia, failure to thrive, hypotonia, and developmental delay, and sometimes have protein aversion and/or vomiting and lethargy after protein intake. Atypical and "benign"/adult methylmalonic acidemia phenotypes are associated with increased, albeit mild, urinary excretion of methylmalonate. Major secondary complications of methylmalonic acidemia include: intellectual impairment (variable); tubulointerstitial nephritis with progressive renal failure; "metabolic stroke" (acute and chronic basal ganglia injury) causing a disabling movement disorder with choreoathetosis, dystonia, and para/quadriparesis; pancreatitis; growth failure; functional immune impairment; and optic nerve atrophy.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 12:109555371
Likely benign
Hetero
Gene:
COL5A2
Variant:
c.2032-39A>T
rsID: rs6414122
Ref Allele: T
Alt Allele: A
Freq: 4.5943%uncommon
CADD: 0.426
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 2:189060822
Benign
Hetero
Gene:
MMAB
Variant:
c.135-23T>C
rsID: rs66580225
Ref Allele: A
Alt Allele: G
Freq: 4.6015%uncommon
CADD: 4.496
ClinVar Submissions (2)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Feb 03, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 12:109571733
Benign/Likely benign
Hetero
Gene:
TWNK
Variant:
c.1102G>A
(p.Val368Ile)
rsID: rs17113613
Ref Allele: G
Alt Allele: A
Freq: 4.6111%uncommon
CADD: 21.3
ClinVar Submissions (6)
Last Evaluated: Jan 30, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 10:100989312
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jan 30, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 10:100989312
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jan 30, 2018
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 6
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 10:100989312
Benign
Hetero
Gene:
SDHB
Variant:
c.201-36G>T
rsID: rs1022580
Ref Allele: C
Alt Allele: A
Freq: 4.6126%uncommon
CADD: 0.349
ClinVar Submissions (2)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 15, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:17033181
Benign
Hetero
Gene:
MFN2
Variant:
c.*1100A>G
rsID: rs41278638
Ref Allele: A
Alt Allele: G
Freq: 4.6302%uncommon
CADD: 8.387
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:12012665
A group of slowly progressive inherited disorders affecting motor and sensory peripheral nerves. Subtypes include HMSNs I-VII. HMSN I and II both refer to CHARCOT-MARIE-TOOTH DISEASE. HMSN III refers to hypertrophic neuropathy of infancy. HMSN IV refers to REFSUM DISEASE. HMSN V refers to a condition marked by a hereditary motor and sensory neuropathy associated with spastic paraplegia (see SPASTIC PARAPLEGIA, HEREDITARY). HMSN VI refers to HMSN associated with an inherited optic atrophy (OPTIC ATROPHIES, HEREDITARY), and HMSN VII refers to HMSN associated with retinitis pigmentosa. (From Adams et al., Principles of Neurology, 6th ed, p1343)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:12012665
Likely benign
Hetero
Gene:
MC1R
Variant:
c.478C>T
(p.Arg160Trp)
rsID: rs1805008
Ref Allele: C
Alt Allele: T
Freq: 4.6318%uncommon
CADD: 22.9
ClinVar Submissions (4)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity, Affects, association, risk factor
Assembly: GRCh38
Chromosome/Position: 16:89919736
OMIM Allelic Variant: 155555.0005
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity, Affects, association, risk factor
Assembly: GRCh38
Chromosome/Position: 16:89919736
OMIM Allelic Variant: 155555.0005
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity, Affects, association, risk factor
Assembly: GRCh38
Chromosome/Position: 16:89919736
OMIM Allelic Variant: 155555.0005
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity, Affects, association, risk factor
Assembly: GRCh38
Chromosome/Position: 16:89919736
OMIM Allelic Variant: 155555.0005
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity, Affects, association, risk factor
Assembly: GRCh38
Chromosome/Position: 16:89919736
OMIM Allelic Variant: 155555.0005
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, conflicting interpretations
Number of Submitters: 4
Clinical Significance: Conflicting interpretations of pathogenicity, Affects, association, risk factor
Assembly: GRCh38
Chromosome/Position: 16:89919736
OMIM Allelic Variant: 155555.0005
Clinically Significant Conflicting/Uncertain
Hetero
Gene:
ANO10
Variant:
c.1682C>T
(p.Thr561Met)
rsID: rs17409162
Ref Allele: G
Alt Allele: A
Freq: 4.6357%uncommon
CADD: 25.2
ClinVar Submissions (4)
Autosomal recessive cerebellar ataxias (ARCA) are a heterogeneous group of rare neurological disorders involving both the central and peripheral nervous system (and in some cases other systems and organs), and characterized by degeneration or abnormal development of the cerebellum and spinal cord and, in most cases, early onset occurring before the age of 20 years.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:43549835
Autosomal recessive spinocerebellar ataxia-10 is an autosomal recessive neurodegenerative disorder with onset in the teenage or young adult years of gait and limb ataxia, dysarthria, and nystagmus associated with marked cerebellar atrophy on brain imaging (summary by Vermeer et al., 2010). Some patients have low levels of coenzyme Q10 (CoQ10) in muscle and may show some clinical improvement with CoQ10 treatment (Balreira et al., 2014).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:43549835
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 3:43549835
Benign/Likely benign
Hetero
Gene:
PLEKHG5
Variant:
c.2428G>A
(p.Gly810Ser)
rsID: rs76625876
Ref Allele: C
Alt Allele: T
Freq: 4.6429%uncommon
CADD: 13.74
ClinVar Submissions (2)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:6468408
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:6468408
Benign/Likely benign
Hetero
Gene:
SDHB
Variant:
c.18C>A
(p.Ala6=)
rsID: rs2746462
Ref Allele: G
Alt Allele: T
Freq: 4.6676%uncommon
CADD: 5.096
ClinVar Submissions (7)
The condition of a pattern of malignancies within a family, but not every individual's necessarily having the same neoplasm. Characteristically the tumor tends to occur at an earlier than average age, individuals may have more than one primary tumor, the tumors may be multicentric, usually more than 25 percent of the individuals in direct lineal descent from the proband are affected, and the cancer predisposition in these families behaves as an autosomal dominant trait with about 60 percent penetrance.
Last Evaluated: Aug 18, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:17054002
A familial syndrome characterised by gastrointestinal stromal tumours and paragangliomas, often at multiple sites. It is a very rare syndrome presenting at a young age. The gastric stromal sarcomas are multifocal and the paragangliomas are multicentric. The clinical spectrum of this syndrome varies widely, depending on the localisation and the size of the tumours. The vast majority of cases are due to germline mutations of the succinate dehydrogenase (SDH) subunit genes SDHB, SDHC and SDHD. Predisposition to developing these tumours is inherited in an autosomal dominant manner with incomplete penetrance.
Last Evaluated: Aug 18, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:17054002
Hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes are characterized by paragangliomas (tumors that arise from neuroendocrine tissues distributed along the paravertebral axis from the base of the skull to the pelvis) and pheochromocytomas (paragangliomas that are confined to the adrenal medulla). Sympathetic paragangliomas cause catecholamine excess; parasympathetic paragangliomas are most often nonsecretory. Extra-adrenal parasympathetic paragangliomas are located predominantly in the skull base and neck (referred to as head and neck PGL [HNPGL]) and sometimes in the upper mediastinum; approximately 95% of such tumors are nonsecretory. In contrast, sympathetic extra-adrenal paragangliomas are generally confined to the lower mediastinum, abdomen, and pelvis, and are typically secretory. Pheochromocytomas, which arise from the adrenal medulla, typically lead to catecholamine excess. Symptoms of PGL/PCC result from either mass effects or catecholamine hypersecretion (e.g., sustained or paroxysmal elevations in blood pressure, headache, episodic profuse sweating, forceful palpitations, pallor, and apprehension or anxiety). The risk for developing metastatic disease is greater for extra-adrenal sympathetic paragangliomas than for pheochromocytomas.
Last Evaluated: Aug 18, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:17054002
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Aug 18, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:17054002
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Aug 18, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 7
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:17054002
Benign
Hetero
Gene:
VDR
Variant:
c.*1979C>G
rsID: rs2544043
Ref Allele: G
Alt Allele: C
Freq: 4.67%uncommon
CADD: 0.453
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 12:47842767
Benign
Hetero
Gene:
EXT2
Variant:
c.-61C>G
rsID: rs12800404
Ref Allele: C
Alt Allele: G
Freq: 4.6907%uncommon
CADD: 21.7
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 11:44095822
Likely benign
Hetero
Gene:
CTNS
Variant:
c.*1665A>G
rsID: rs112317698
Ref Allele: A
Alt Allele: G
Freq: 4.6971%uncommon
CADD: 2.075
ClinVar Submissions (1)
Cystinosis comprises three allelic phenotypes: Nephropathic cystinosis in untreated children is characterized by renal Fanconi syndrome, poor growth, hypophosphatemic/calcipenic rickets, impaired glomerular function resulting in complete glomerular failure, and accumulation of cystine in almost all cells, leading to cellular dysfunction with tissue and organ impairment. The typical untreated child has short stature, rickets, and photophobia. Failure to thrive is generally noticed after approximately age six months; signs of renal tubular Fanconi syndrome (polyuria, polydipsia, dehydration, and acidosis) appear as early as age six months; corneal crystals can be present before age one year and are always present after age 16 months. Prior to the use of renal transplantation and cystine-depleting therapy, the life span in nephropathic cystinosis was no longer than ten years. With these interventions, affected individuals can survive at least into the mid-forties or fifties with satisfactory quality of life. Intermediate cystinosis is characterized by all the typical manifestations of nephropathic cystinosis, but onset is at a later age. Renal glomerular failure occurs in all untreated affected individuals, usually between ages 15 and 25 years. The non-nephropathic (ocular) form of cystinosis is characterized clinically only by photophobia resulting from corneal cystine crystal accumulation.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 17:3662034
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 17:3662034
Likely benign
Hetero
Gene:
DYNC2H1
Variant:
c.911A>T
(p.Gln304Leu)
rsID: rs12146610
Ref Allele: A
Alt Allele: T
Freq: 4.7337%uncommon
CADD: 23.1
ClinVar Submissions (5)
Asphyxiating thoracic dystrophy, also known as Jeune syndrome, is an inherited disorder of bone growth characterized by a narrow chest, short ribs, shortened bones in the arms and legs, short stature, and extra fingers and toes (polydactyly). Additional skeletal abnormalities can include unusually shaped collarbones (clavicles) and pelvic bones, and and cone-shaped ends of the long bones in the arms and legs. Many infants with this condition are born with an extremely narrow, bell-shaped chest that can restrict the growth and expansion of the lungs. Life-threatening problems with breathing result, and people with asphyxiating thoracic dystrophy may live only into infancy or early childhood. However, in people who survive beyond the first few years, the narrow chest and related breathing problems can improve with age.Some people with asphyxiating thoracic dystrophy are born with less severe skeletal abnormalities and have only mild breathing difficulties, such as rapid breathing or shortness of breath. These individuals may live into adolescence or adulthood. After infancy, people with this condition may develop life-threatening kidney (renal) abnormalities that cause the kidneys to malfunction or fail. Heart defects and a narrowing of the airway (subglottic stenosis) are also possible. Other, less common features of asphyxiating thoracic dystrophy include liver disease, fluid-filled sacs (cysts) in the pancreas, dental abnormalities, and an eye disease called retinal dystrophy that can lead to vision loss.
Last Evaluated: May 01, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:103117775
A rare congenital lethal syndrome characterized by the presence of extra fingers and toes and short ribs, the latter resulting in inability of the lungs to expand. The newborn dies shortly after birth.
Last Evaluated: May 01, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:103117775
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: May 01, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:103117775
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: May 01, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 11:103117775
Low clinical importance, Uncertain benign — Presumed benign.
Benign/Likely benign
Hetero
Gene:
MOCS1
Variant:
c.*1755C>T
rsID: rs7758412
Ref Allele: G
Alt Allele: A
Freq: 4.7369%uncommon
CADD: 0.139
ClinVar Submissions (1)
Molybdenum cofactor deficiency (MOCOD) is a rare autosomal recessive metabolic disorder characterized by onset in infancy of poor feeding, intractable seizures, and severe psychomotor retardation. Characteristic biochemical abnormalities include decreased serum uric acid and increased urine sulfite levels due to the combined enzymatic deficiency of xanthine dehydrogenase (XDH; 607633) and sulfite oxidase (SUOX; 606887), both of which use molybdenum as a cofactor. Most affected individuals die in early childhood (summary by Reiss, 2000; Reiss et al., 2011). Genetic Heterogeneity of Molybdenum Cofactor Deficiency See also MOCOD, complementation group B (MOCODB; 252160), caused by mutation in the MOCS2 gene (602708) on chromosome 5q11; and MOCOD, complementation group C (MOCODC; 615501), caused by mutation in the GPHN gene (603930) on chromosome 14q24.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 6:39905370
Likely benign
Hetero
Gene:
ATP2C1
Variant:
c.6+15C>G
rsID: rs112703671
Ref Allele: C
Alt Allele: G
Freq: 4.7576%uncommon
CADD: 13.51
ClinVar Submissions (2)
Hailey-Hailey disease, also known as benign chronic pemphigus, is a rare autosomal dominant cutaneous disorder that usually becomes manifest in the third or fourth decade of life with erythema, vesicles, and erosions involving the body folds, particularly the groin and axillary regions. Other sites of the body, such as the neck, perianal, and submammary regions, may likewise be affected (summary by Poblete-Gutierrez et al., 2004). This disorder was first described by the dermatologist brothers Hailey and Hailey (1939).
Last Evaluated: May 19, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 3:130894790
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: May 19, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 2
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 3:130894790
Benign
Hetero
Gene:
DSG2
Variant:
c.2137G>A
(p.Glu713Lys)
rsID: rs79241126
Ref Allele: G
Alt Allele: A
Freq: 4.7703%uncommon
CADD: 8.462
ClinVar Submissions (8)
Arrhythmogenic right ventricular cardiomyopathy (ARVC) – previously referred to as arrhythmogenic right ventricular dysplasia (ARVD) – is characterized by progressive fibrofatty replacement of the myocardium that predisposes to ventricular tachycardia and sudden death in young individuals and athletes. It primarily affects the right ventricle, and it may also involve the left ventricle. The presentation of disease is highly variable even within families, and some affected individuals may not meet established clinical criteria. The mean age at diagnosis is 31 years (±13; range: 4-64 years).
Last Evaluated: May 17, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 18:31542655
Last Evaluated: May 17, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 18:31542655
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: May 17, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 18:31542655
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: May 17, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 8
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 18:31542655
Benign/Likely benign
Hetero
Gene:
ARSA
Variant:
c.585G>T
(p.Trp195Cys)
rsID: rs6151415
Ref Allele: C
Alt Allele: A
Freq: 4.7886%uncommon
CADD: 24.8
ClinVar Submissions (5)
Arylsulfatase A deficiency (also known as metachromatic leukodystrophy or MLD) is characterized by three clinical subtypes: late-infantile MLD, juvenile MLD, and adult MLD. Age of onset within a family is usually similar. The disease course may be from several years in the late-infantile-onset form to decades in the juvenile- and adult-onset forms. Late-infantile MLD. Onset is before age 30 months. Typical presenting findings include weakness, hypotonia, clumsiness, frequent falls, toe walking, and dysarthria. As the disease progresses, language, cognitive, and gross and fine motor skills regress. Later signs include spasticity, pain, seizures, and compromised vision and hearing. In the final stages, children have tonic spasms, decerebrate posturing, and general unawareness of their surroundings. Juvenile MLD. Onset is between age 30 months and 16 years. Initial manifestations include decline in school performance and emergence of behavioral problems, followed by gait disturbances. Progression is similar to but slower than in the late-infantile form. Adult MLD. Onset occurs after age 16 years, sometimes not until the fourth or fifth decade. Initial signs can include problems in school or job performance, personality changes, emotional lability, or psychosis; in others, neurologic symptoms (weakness and loss of coordination progressing to spasticity and incontinence) or seizures initially predominate. Peripheral neuropathy is common. Disease course is variable – with periods of stability interspersed with periods of decline – and may extend over two to three decades. The final stage is similar to earlier-onset forms.
Last Evaluated: Jul 25, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 22:50626933
The term 'not provided' is registered in MedGen to support identification of submissions to ClinVar for which no condition was named when assessing the variant. 'not provided' differs from 'not specified', which is used when a variant is asserted to be benign, likely benign, or of uncertain significance for conditions that have not been specified.
Last Evaluated: Jul 25, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 22:50626933
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jul 25, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 22:50626933
Benign/Likely benign
Hetero
Gene:
COL7A1
Variant:
c.8305-20G>C
rsID: rs17256786
Ref Allele: C
Alt Allele: G
Freq: 4.8014%uncommon
CADD: 1.294
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 3:48566583
Benign
Hetero
Gene:
ACTN2
Variant:
c.*700A>G
rsID: rs12733179
Ref Allele: A
Alt Allele: G
Freq: 4.8189%uncommon
CADD: 2.619
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:236763319
A condition in which the myocardium is hypertrophied without an obvious cause. The hypertrophy is generally asymmetric and may be associated with obstruction of the ventricular outflow tract.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:236763319
Likely benign
Hetero
Gene:
OCA2
Variant:
c.1256G>A
(p.Arg419Gln)
rsID: rs1800407
Ref Allele: C
Alt Allele: T
Freq: 4.8332%uncommon
CADD: 28.7
ClinVar Submissions (4)
Oculocutaneous albinism is a group of conditions that affect coloring (pigmentation) of the skin, hair, and eyes. Affected individuals typically have very fair skin and white or light-colored hair. Long-term sun exposure greatly increases the risk of skin damage and skin cancers, including an aggressive form of skin cancer called melanoma, in people with this condition. Oculocutaneous albinism also reduces pigmentation of the colored part of the eye (the iris) and the light-sensitive tissue at the back of the eye (the retina). People with this condition usually have vision problems such as reduced sharpness; rapid, involuntary eye movements (nystagmus); and increased sensitivity to light (photophobia).Researchers have identified multiple types of oculocutaneous albinism, which are distinguished by their specific skin, hair, and eye color changes and by their genetic cause. Oculocutaneous albinism type 1 is characterized by white hair, very pale skin, and light-colored irises. Type 2 is typically less severe than type 1; the skin is usually a creamy white color and hair may be light yellow, blond, or light brown. Type 3 includes a form of albinism called rufous oculocutaneous albinism, which usually affects dark-skinned people. Affected individuals have reddish-brown skin, ginger or red hair, and hazel or brown irises. Type 3 is often associated with milder vision abnormalities than the other forms of oculocutaneous albinism. Type 4 has signs and symptoms similar to those seen with type 2.Several additional types of this disorder have been proposed, each affecting one or a few families.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign, Affects
Assembly: GRCh38
Chromosome/Position: 15:27985172
OMIM Allelic Variant: 611409.0012
Genetic Heterogeneity of Variation in Skin/Hair/Eye Pigmentation Multiple genes influence normal human skin, hair, and/or eye pigmentation. Pigmentation phenotypes influenced by variation in the OCA2 gene are termed SHEP1. The SHEP2 association (266300) is determined by variation at the MC1R locus (155555) and describes a phenotype predominantly characterized by red hair and fair skin. SHEP3 (601800) encompasses pigment variation influenced by the TYR gene (606933); SHEP4 (113750), that influenced by the SLC24A5 gene (609802). Variation in the SLC45A2 (606202) and SLC24A4 (609840) genes result in the phenotypic associations SHEP5 (227240) and SHEP6 (210750), respectively. Sequence variation thought to affect expression of KITLG (184745) results in the SHEP7 (611664) phenotypic association. SHEP8 (611724) is associated with variation in the IRF4 gene (601900). Polymorphism in the 3-prime untranslated region of the ASIP gene (600201) influences the SHEP9 association (611742). The SHEP10 association (612267) comprises variation in the TPCN2 gene (612163), and SHEP11 (612271) is associated with polymorphism near the TYRP1 gene (115501).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign, Affects
Assembly: GRCh38
Chromosome/Position: 15:27985172
OMIM Allelic Variant: 611409.0012
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign, Affects
Assembly: GRCh38
Chromosome/Position: 15:27985172
OMIM Allelic Variant: 611409.0012
Low clinical importance, Likely benign — This variant is associated with eye color, as is OCA2 R305W. Individuals with this variant are reported to be more likely to have green/hazel eyes as opposed to blue/gray eyes. Other variants in this gene are associated with oculocutaneous albinism (albinism which involves skin and eyes).
Benign/Likely benign, Affects
Hetero
Gene:
DMD
Variant:
c.4234-13A>G
rsID: rs41303181
Ref Allele: T
Alt Allele: C
Freq: 4.8332%uncommon
ClinVar Submissions (5)
The dystrophinopathies cover a spectrum of X-linked muscle disease ranging from mild to severe that includes Duchenne muscular dystrophy, Becker muscular dystrophy, and DMD-associated dilated cardiomyopathy (DCM). The mild end of the spectrum includes the phenotypes of asymptomatic increase in serum concentration of creatine phosphokinase (CK) and muscle cramps with myoglobinuria. The severe end of the spectrum includes progressive muscle diseases that are classified as Duchenne/Becker muscular dystrophy when skeletal muscle is primarily affected and as DMD-associated dilated cardiomyopathy (DCM) when the heart is primarily affected. Duchenne muscular dystrophy (DMD) usually presents in early childhood with delayed motor milestones including delays in walking independently and standing up from a supine position. Proximal weakness causes a waddling gait and difficulty climbing stairs, running, jumping, and standing up from a squatting position. DMD is rapidly progressive, with affected children being wheelchair dependent by age 12 years. Cardiomyopathy occurs in almost all individuals with DMD after age 18 years. Few survive beyond the third decade, with respiratory complications and progressive cardiomyopathy being common causes of death. Becker muscular dystrophy (BMD) is characterized by later-onset skeletal muscle weakness. With improved diagnostic techniques, it has been recognized that the mild end of the spectrum includes men with onset of symptoms after age 30 years who remain ambulatory even into their 60s. Despite the milder skeletal muscle involvement, heart failure from DCM is a common cause of morbidity and the most common cause of death in BMD. Mean age of death is in the mid-40s. DMD-associated DCM is characterized by left ventricular dilation and congestive heart failure. Females heterozygous for a DMD pathogenic variant are at increased risk for DCM.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: X:32390194
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 5
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: X:32390194
Benign/Likely benign
Homo
Gene:
CNGB3
Variant:
c.1179-38T>C
rsID: rs3735969
Ref Allele: A
Alt Allele: G
Freq: 4.8667%uncommon
CADD: 0.019
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 8:86632931
Benign
Hetero
Gene:
PLEKHG5
Variant:
c.*697C>T
rsID: rs3176900
Ref Allele: G
Alt Allele: A
Freq: 4.8683%uncommon
CADD: 4.264
ClinVar Submissions (1)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 1:6466866
Likely benign
Hetero
Gene:
LOXHD1
Variant:
c.6398G>A
(p.Arg2133His)
rsID: rs74316327
Ref Allele: C
Alt Allele: T
Freq: 4.8834%uncommon
CADD: 23.9
ClinVar Submissions (3)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: May 09, 2017
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 18:46477710
Benign
Hetero
Gene:
PMP22
Variant:
c.*228G>A
rsID: rs1804193
Ref Allele: C
Alt Allele: T
Freq: 4.8906%uncommon
CADD: 17.08
ClinVar Submissions (1)
Charcot-Marie-Tooth disease encompasses a group of disorders called hereditary sensory and motor neuropathies that damage the peripheral nerves. Peripheral nerves connect the brain and spinal cord to muscles and to sensory cells that detect sensations such as touch, pain, heat, and sound. Damage to the peripheral nerves that worsens over time can result in alteration or loss of sensation and wasting (atrophy) of muscles in the feet, legs, and hands.Charcot-Marie-Tooth disease usually becomes apparent in adolescence or early adulthood, but onset may occur anytime from early childhood through late adulthood. Symptoms of Charcot-Marie-Tooth disease vary in severity and age of onset even among members of the same family. Some people never realize they have the disorder because their symptoms are so mild, but most have a moderate amount of physical disability. A small percentage of people experience severe weakness or other problems which, in very rare cases, can be life-threatening. In most affected individuals, however, Charcot-Marie-Tooth disease does not affect life expectancy.Typically, the earliest symptoms of Charcot-Marie-Tooth disease result from muscle atrophy in the feet. Affected individuals may have foot abnormalities such as high arches (pes cavus), flat feet (pes planus), or curled toes (hammer toes). They often have difficulty flexing the foot or walking on the heel of the foot. These difficulties may cause a higher than normal step (steppage gait) and increase the risk of ankle injuries and tripping. As the disease worsens, muscles in the lower legs usually weaken, but leg and foot problems rarely require the use of a wheelchair.Affected individuals may also develop weakness in the hands, causing difficulty with daily activities such as writing, fastening buttons, and turning doorknobs. People with Charcot-Marie-Tooth disease typically experience a decreased sensitivity to touch, heat, and cold in the feet and lower legs, but occasionally feel aching or burning sensations. In rare cases, affected individuals have loss of vision or gradual hearing loss that sometimes leads to deafness.There are several types of Charcot-Marie-Tooth disease, which are differentiated by their effects on nerve cells and patterns of inheritance. Type 1 (CMT1) is characterized by abnormalities in myelin, the fatty substance that covers nerve cells, protecting them and helping to transmit nerve impulses. These abnormalities slow the transmission of nerve impulses and can affect the health of the nerve fiber. Type 2 (CMT2) is characterized by abnormalities in the fiber, or axon, that extends from a nerve cell body to muscles or to sense organs. These abnormalities reduce the strength of the nerve impulse. In forms of Charcot-Marie-Tooth disease classified as intermediate type, the nerve impulses are both slowed and reduced in strength, probably due to abnormalities in both myelin and axons. Type 4 (CMT4) is distinguished from the other types by its pattern of inheritance; it can affect either the axons or the myelin. Type X Charcot-Marie-Tooth disease (CMTX) is caused by mutations in genes on the X chromosome, one of the two sex chromosomes. Within the various types of Charcot-Marie-Tooth disease, subtypes (such as CMT1A, CMT1B, CMT2A, CMT4A, and CMTX1) indicate different genetic causes.Sometimes other, historical names are used to refer to particular forms of Charcot-Marie-Tooth disease. For example, Roussy-Levy syndrome is a form of CMT11 with the additional feature of rhythmic shaking (tremors). Dejerine-Sottas syndrome is a term sometimes used to describe a severe, early childhood form of Charcot-Marie-Tooth disease; it is also sometimes called type 3 (CMT3). Depending on the specific gene that is altered, this severe, early-onset form of the disorder may also be classified as CMT1 or CMT4. CMTX5 is also known as Rosenberg-Chutorian syndrome.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 17:15230689
Hereditary neuropathy with liability to pressure palsies (HNPP) is characterized by repeated focal pressure neuropathies such as carpal tunnel syndrome and peroneal palsy with foot drop. The first attack usually occurs in the second or third decade. Recovery from acute neuropathy is often complete; when recovery is not complete, the resulting disability is usually mild. Some affected individuals also have signs of a mild to moderate peripheral neuropathy.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 17:15230689
Likely benign
Hetero
Gene:
STX16
Variant:
c.-350C>A
rsID: rs41296205
Ref Allele: C
Alt Allele: A
Freq: 4.893%uncommon
CADD: 6.331
ClinVar Submissions (1)
Autosomal dominant pseudohypoaldosteronism type I is characterized by salt wasting resulting from renal unresponsiveness to mineralocorticoids. Patients may present with neonatal renal salt wasting with hyperkalaemic acidosis despite high aldosterone levels. These patients improve with age and usually become asymptomatic without treatment. Some adult patients with the disorder may have elevated aldosterone levels, but no history of clinical disease. This observation suggests that only those infants whose salt homeostasis is stressed by intercurrent illness and volume depletion develop clinically recognized PHA I (summary by Geller et al., 1998). Autosomal recessive pseudohypoaldosteronism type I (PHA1B; 264350), caused by mutation in any one of 3 genes encoding the epithelial sodium channel (ENaC), is a similar but more severe systemic disorder with persistence into adulthood.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 20:58651657
Benign
Hetero
Gene:
AP3B1
Variant:
c.1969-10G>A
rsID: rs77009095
Ref Allele: C
Alt Allele: T
Freq: 4.9439%uncommon
CADD: 9.102
ClinVar Submissions (3)
Hermansky-Pudlak syndrome (HPS) is characterized by oculocutaneous albinism, a bleeding diathesis, and, in some individuals, pulmonary fibrosis, granulomatous colitis, or immunodeficiency. Ocular findings include reduced iris pigment with iris transillumination, reduced retinal pigment, foveal hypoplasia with significant reduction in visual acuity (usually in the range of 20/50 to 20/400), nystagmus, and increased crossing of the optic nerve fibers. Hair color ranges from white to brown; skin color ranges from white to olive and is usually a shade lighter than that of other family members. The bleeding diathesis can result in variable bruising, epistaxis, gingival bleeding, postpartum hemorrhage, colonic bleeding, and prolonged bleeding with menses or after tooth extraction, circumcision, and other surgeries. Pulmonary fibrosis, a restrictive lung disease, typically causes symptoms in the early thirties and can progress to death within a decade. Granulomatous colitis is severe in about 15% of affected individuals. Neutropenia and/or immune defects occur primarily in individuals with pathogenic variants in AP3B1 and AP3D1.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 5:78116244
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 5:78116244
Benign/Likely benign
Hetero
Gene:
DIAPH1
Variant:
c.117+14C>T
rsID: rs2074913
Ref Allele: G
Alt Allele: A
Freq: 4.9535%uncommon
CADD: 18.02
ClinVar Submissions (4)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 5:141618784
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 4
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 5:141618784
Benign/Likely benign
Hetero
Gene:
AGL
Variant:
c.3700+32T>C
rsID: rs834575
Ref Allele: T
Alt Allele: C
Freq: 4.9575%uncommon
CADD: 2.031
ClinVar Submissions (1)
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: -
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 1:99902826
Benign
Hetero
Gene:
RNASET2
Variant:
c.21C>T
(p.Arg7=)
rsID: rs12193095
Ref Allele: G
Alt Allele: A
Freq: 4.9631%uncommon
CADD: 5.87
ClinVar Submissions (1)
RNAse T2-deficient leukoencephalopathy is a disorder that affects the brain. People with RNAse T2-deficient leukoencephalopathy have neurological problems that become apparent during infancy; the problems generally do not worsen over time (progress). Most affected individuals have severe intellectual disability; muscle stiffness (spasticity); and a delay in developing motor skills such as sitting, crawling, and walking. Some do not learn to walk, and most do not develop the ability to speak. Other neurological features that can occur in RNAse T2-deficient leukoencephalopathy include hearing loss caused by abnormalities in the inner ear (sensorineural deafness), seizures, involuntary writhing movements of the hands (athetosis), uncontrolled muscle tensing (dystonia), and involuntary eye movements (nystagmus). In addition to the neurological problems associated with this disorder, some affected individuals have unusual facial features sometimes described as a "doll-like face."The neurological problems in this disorder are caused by abnormalities in the brain. People with this condition have leukoencephalopathy, an abnormality of the brain's white matter that can be detected with medical imaging. White matter consists of nerve fibers covered by a fatty substance called myelin. Myelin insulates nerve fibers and promotes the rapid transmission of nerve impulses. In people with RNAse T2-deficient leukoencephalopathy, myelin is not made in sufficient amounts during development, leading to patchy white matter abnormalities (lesions) in the brain. In addition, individuals with RNAse T2-deficient leukoencephalopathy may have cysts in regions of the brain called the temporal lobes and enlargement of the fluid-filled cavities (ventricles) near the center of the brain. The white matter lesions are primarily concentrated around the cysts and the ventricles. An abnormally small head and brain size (microcephaly) often occurs in this disorder.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Likely benign
Assembly: GRCh38
Chromosome/Position: 6:166956162
Likely benign
Hetero
Gene:
ANKH
Variant:
c.-4G>A
rsID: rs78431233
Ref Allele: C
Alt Allele: T
Freq: 4.983%uncommon
CADD: 18.95
ClinVar Submissions (1)
Presence of CALCIUM PYROPHOSPHATE in the connective tissues such as the cartilaginous structures of joints. When accompanied by GOUT-like symptoms, it is referred to as pseudogout.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 5:14871451
Craniometadiaphyseal dysplasia (CRMDD) is characterized clinically by macrocephaly with frontal prominence, dental hypoplasia, and increased bone fragility. Diagnostic radiologic features include thin bones in the superior part of calvaria with prominent wormian bones, diaphyseal widening of the long tubular bones in early childhood with wide undermineralized metaphyses in older individuals, widened ribs and clavicles, and broadening of short tubular bones with increased transparency and thin cortices (summary by Dhar et al., 2010).
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, single submitter
Number of Submitters: 1
Clinical Significance: Benign
Assembly: GRCh38
Chromosome/Position: 5:14871451
Benign
Hetero
Gene:
MFN2
Variant:
c.1569C>T
(p.Ser523=)
rsID: rs1042837
Ref Allele: C
Alt Allele: T
Freq: 4.9854%uncommon
CADD: 12.42
ClinVar Submissions (3)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:12005784
A group of slowly progressive inherited disorders affecting motor and sensory peripheral nerves. Subtypes include HMSNs I-VII. HMSN I and II both refer to CHARCOT-MARIE-TOOTH DISEASE. HMSN III refers to hypertrophic neuropathy of infancy. HMSN IV refers to REFSUM DISEASE. HMSN V refers to a condition marked by a hereditary motor and sensory neuropathy associated with spastic paraplegia (see SPASTIC PARAPLEGIA, HEREDITARY). HMSN VI refers to HMSN associated with an inherited optic atrophy (OPTIC ATROPHIES, HEREDITARY), and HMSN VII refers to HMSN associated with retinitis pigmentosa. (From Adams et al., Principles of Neurology, 6th ed, p1343)
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:12005784
The term 'not specified' was created for use in ClinVar so that submitters can convey the concept that a variant is benign, likely benign, or of uncertain significance for an unspecified set of disorders. This usage was introduced in 2014 to replace AllHighlyPenetrant.
Last Evaluated: Jun 14, 2016
Review Status: criteria provided, multiple submitters, no conflicts
Number of Submitters: 3
Clinical Significance: Benign/Likely benign
Assembly: GRCh38
Chromosome/Position: 1:12005784
Benign/Likely benign
Hetero